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HoC_dynamic_1_shot_test

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HoC_dynamic_1_shot100

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Chronic inflammation is a critical component in breast cancer progression . Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines ( IL-1 , IL-6 , TNF-α ) , chemotactic cytokines and their receptors ( CXCR4 , CXCL12 , CXCL8 ) and angiogenic factors ( VEGF ) that often overcome the effect of anti-inflammatory molecules ( IL-4 , IL-10 ) thus evading the host's antitumor immunity . Detailed knowledge , therefore , of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer . HIF-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1α is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors . The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells . Functional crosstalk between HIF-1α and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions . In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation , we investigated the role of the two common p53 and HIF-1α co-regulators SRC-1 and SIRT-1 , in the expression of the highly potent metastatic chemokine receptor CXCR4 . Both SRC-1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND Inactivation of p53 is involved in arsenite-induced tumorigenesis ; however , the molecular mechanisms remain poorly understood . OBJECTIVE We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fibroblast ( HELF ) cells . METHODS Anchorage-independent growth assays were performed , and tumorigenicity in intact animals was assessed to confirm arsenite-induced neoplastic transformation . We determined the levels and functions of p53 , nuclear factor-kappa B ( NF-B ; a key transcriptional regulator ) , and mot-2 ( a p53 inhibitor ) and their relationships in arsenite-induced transformed HELF cells by two-dimensional electrophoresis , reverse-transcriptase polymerase chain reaction , Western blot , immunofluorescence , and co-immunoprecipitation assays . RESULTS Exposure of HELF cells to low levels of arsenite increased their proliferation rate and anchorage-independent growth and disrupted normal contact inhibition . When introduced into nude mice , transformed cells were tumorigenic . We used proteomic analysis to identify proteins with altered expression between untreated and arsenite-exposed cells . We found decreased expression of NF-B repressing factor ( NKRF ; an inhibitor of NF-B-mediated gene transcription ) , increased expression of mot-2 , and increased activation of NF-B . Changes in cells exposed to 1.0 microM arsenite were more marked than changes in cells exposed to 0.5 or 2.0 microM arsenite . Inactivation of NF-B prevented malignant transformation induced by 1.0 microM arsenite . Moreover , we also identified a mechanism whereby NF-B regulated p53 . Specifically , activation of NF-B up-regulated mot-2 expression , which prevented nuclear translocation of p53 and switched the binding preference of the p53 and NF-B coactivator CBP [ cyclic AMP-responsive element binding protein ( CREB ) binding protein ] from p53 to NF-B . CONCLUSIONS mot-2-mediated cross talk between NF-B and p53 appears to be involved in arsenite-induced tumorigenesis of HELF cells . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot101

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Among several types of DNA lesions , the DNA double strand breaks ( DSBs ) are one of the most deleterious and harmful . Mammalian cells mount a coordinated response to DSBs with the aim of appropriately repair the DNA damage . Indeed , failure of the DNA damage response ( DDR ) can lead to the development of cancer-prone genetic diseases . The identification and development of drugs targeting proteins involved in the DDR is even more investigated , as it gives the possibility to specifically target cancer cells . Indeed , the administration of DNA repair inhibitors could be combined with chemo- and radiotherapy , thus improving the eradication of tumor cells . Here , we provide an overview about DSBs damage response , focusing on the role of the DSBs repair mechanisms , of chromatin modifications , and of the cancer susceptibility gene BRCA1 which plays a multifunctional role in controlling genome integrity . Moreover , the most investigated DSBs enzyme inhibitors tested as potential therapeutic agents for anti-cancer therapy are reported . OUTPUT: genomic instability and mutation INPUT: DNA double strand breaks ( DSBs ) arise from spontaneous DNA damage due to metabolic activities or from direct and indirect damaging effects of stress . DSBs are also formed transiently during such processes as replication , transcription , and DNA repair . The level of DSBs positively correlates with the activities of homologous and nonhomologous DNA repair pathways , which in turn inversely correlate with methylation levels and chromatin structure . Thus , measurement of strand breaks can provide an informative picture of genome stability of a given cell . The use of random oligonucleotide-primed synthesis for the analysis of DSB levels is described . Applications of the assay for quantitative detection of 3'OH , 3'P , or DNA strand breaks at a cleavage site of the deoxyribose residue are discussed . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot102

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Abstract The use of immunotherapeutics in melanoma has received much attention , and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation . Cytotoxic T lymphocyte-associated antigen 4 ( CTLA-4 ) serves as a negative regulator of immunity . Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses . Treatment with CTLA-4 blocking antibodies , however , is not without potential toxicities . Autoimmune side-effects , the most common being colitis-associated diarrhea , are frequently associated with clinical responses . In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities , we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor ( GVAX ; Cell Genesys , South San Francisco , CA , USA ) with periodic infusions of CTLA-4 blocking antibodies . This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients . Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells ( T(regs) ) . Effective anti-tumor immunity and serious autoimmunity can be disassociated . Further targeting of anti-tumor T(regs)in combinatorial therapy approaches may be a rich avenue of future investigation . OUTPUT: avoiding immune destruction;resisting cell death INPUT: Although the immunomodulatory effects of many herbs have been extensively studied , research related to possible immunomodulatory effects of various spices is relatively scarce . Here , the potential immunomodulatory effects of black pepper and cardamom are investigated . Our data show that black pepper and cardamom aqueous extracts significantly enhance splenocyte proliferation in a dose-dependent , synergistic fashion . Enzyme-linked immunosorbent assay experiments reveal that black pepper and cardamom significantly enhance and suppress , respectively , T helper ( Th)1 cytokine release by splenocytes . Conversely , Th2 cytokine release by splenocytes is significantly suppressed and enhanced by black pepper and cardamom , respectively . Experimental evidence suggests that black pepper and cardamom extracts exert pro-inflammatory and anti-inflammatory roles , respectively . Consistently , nitric oxide production by macrophages is significantly augmented and reduced by black pepper and cardamom , respectively . Remarkably , it is evident that black pepper and cardamom extracts significantly enhance the cytotoxic activity of natural killer cells , indicating their potential anti-cancer effects . Our findings strongly suggest that black pepper and cardamom exert immunomodulatory roles and antitumor activities , and hence they manifest themselves as natural agents that can promote the maintenance of a healthy immune system . We anticipate that black pepper and cardamom constituents can be used as potential therapeutic tools to regulate inflammatory responses and prevent/attenuate carcinogenesis . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot103

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Spindle cell oncocytoma ( SCO ) of the pituitary gland is a relatively recently established , very rare subtype of adenohypophysis tumours that was introduced as a distinct clinicopathological entity in the fourth edition of WHO classification of the central nervous system tumours ( 2007 ) . It is non-endocrine neoplasm of the anterior pituitary that occurs in adults and usually follows a benign clinical course , corresponding to WHO grade I. Up to now , pituitary SCO have been reported occasionally and only 14 cases of SCO have been documented in the literature . Because of their rarity , the pathogenesis and natural history of these tumours have not been fully characterized . We report two additional cases of SCO occurring in females aged 63 years ( Case 1 ) and 65 years ( Case 2 ) , who presented with pan-hypopituitarism , headache and visual field defect . In both cases , the magnetic resonance imaging showed solid sellar mass of moderate size with suprasellar extension . The clinical and radiological features suggested non-functioning pituitary macroadenomas without evidence of invasive growth . One patient presented with tumour recurrence 3 years after undergoing the previous surgical removal of tumour , which was initially misdiagnosed as schwannoma . The first tumour was removed by transsphenoidal surgery and the second one by frontal craniotomy . Histologically and immunohistochemically , both tumours displayed the features typical for SCO of the pituitary . They were composed of interwoven fascicles of spindle cells exhibiting abundant eosinophilic cytoplasm of oncocytic or granular appearance . Mitoses were rarely observed and necrosis was absent . In one case , the advanced lymphocytic infliltration was observed within neoplastic tissue . The tumour cells exhibited immunoreactivity for S-100 protein , galectin-3 , vimentin and epithelial membrane antigen but they were negative for GFAP , anterior pituitary neuroendocrine markers ( prolactin , growth hormone , TSH , ACTH , FSH , LH ) , chromogranin , synaptophysin , cytokeratin CK ( AE1/AE3 ) , smooth muscle actin , desmin , CD34 and CD68 . MIB1 labeling index did not exceed 10% . Ultrastructurally , the tumour cells were rich in mitochondria with lamellar cristae . Moreover , in Case 2 some tumour cells showed a number of giant mitochondria with severely destructed internal matrix . Spindle cell oncocytoma of the anterior pituitary is often misdiagnosed entity of uncertain histogenesis . It should be considered in the differential diagnosis of various sellar-region lesions of oncocytic morphology . OUTPUT: resisting cell death INPUT: 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine ( ECyd ) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers . The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells . Here , we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer ( NPC ) . In a panel of 6 NPC cell lines , ECyd effectively inhibited cellular proliferation at nM concentrations ( IC(50) : approximately 13-44nM ) . Moreover , cisplatin-resistant NPC cells were highly sensitive to ECyd ( at nM concentration ) . The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest , PARP cleavage ( a hallmark of apoptosis ) and Bcl-2 downregulation , indicating induction of apoptosis by ECyd in NPC cells . Unexpectedly , ECyd-induced significant downregulation of TIGAR , a newly described dual regulator of apoptosis and glycolysis . More importantly , this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH , the major reducing power critically required for cell proliferation and survival . We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd . Indeed , overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition , demonstrating a novel mechanistic action of ECyd on TIGAR . We demonstrated for the first time that an RNA-directed nucleoside analog , ECyd , exerts its antitumor activity via downregulation of a novel regulator of apoptosis , TIGAR . Moreover , ECyd may represent a novel therapy for NPC . OUTPUT:

resisting cell death;cellular energetics

HoC_dynamic_1_shot104

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVE To study the clinicopathologic features , immunophenotype and ultrastructural features of sinonasal inflammatory myofibroblastic tumors ( IMT ) . METHODS The clinical and histologic features of 5 cases of sinonasal IMT were reviewed . Immunohistochemical study for vimentin , MSA , SMA , calponin , h-caldesmon , desmin , ALK , fibronectin , CK , S-100 and Ki-67 was carried out . Ultrastructural examination was also performed in two of the cases . RESULTS The patients age ranged from 28 to 62 years ( mean = 43 years ) . The male-to-female ratio was 2:3 . The clinical presentation included nasal obstruction , nasal discharge , nasal bleeding , facial pain , facial swelling , toothache and tear overflow . All of the 5 patients suffered from disease relapses ; and 4 of them had recurrences for more than 5 times . One patient had lymph node metastasis and 3 patients died of the disease . Histologically , the tumor cells were arranged in interlacing fascicles and sometimes haphazard in fashion . They were spindly in shape , cytoplasm eosinophilic with mild nuclear atypia and a low mitotic activity . The intervening stroma was myxoid in appearance accompanied by lymphocyte and plasma cell infiltration , abundant blood vessels and focal collagenized areas . In 3 of the recurrent cases , the tumor cells displayed increased nuclear atypia and mitotic activity ( average about 5 to 6 per 10 high-power fields ) , accompanied by patchy necrosis , less inflammatory cell infiltration and focal sarcomatous changes . Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin . SMA , MSA , calponin and fibronectin were variably expressed . Desmin was weakly positive in 1 case . The staining for h-caldesmon , ALK , S-100 and CK was negative . The Ki-67 proliferation index increased with tumor recurrences . Electron microscopy revealed abundant rough endoplasmic reticulum and dense body formation in the cytoplasm . There were an increased amount of collagen fibers in the stroma . CONCLUSIONS IMT rarely occurs in nasal cavity and paranasal sinuses . The tumor is prone to local invasion and recurrences , with subsequent progression to frank malignancy and distant metastasis , resulting in high mortality and poor prognosis . Complete surgical resection remains the main modality of treatment . OUTPUT: activating invasion and metastasis;resisting cell death;tumor promoting inflammation;sustaining proliferative signaling INPUT: Ovarian smooth muscle tumors are a very rare type of ovarian tumor . In this paper , we report the case of a 62-year-old woman who had a huge smooth muscle tumor of the right ovary . The values of all the serum tumor markers were within normal limit . The tumor measured 25 cm in diameter and weighed 6,200 g . Histological examination revealed that coagulative cellular atypia was moderate to severe , necrosis was not present and mitotic index was low . According to the criteria for the evaluation of the uterine smooth muscle tumors , this huge tumor was diagnosed as atypical leiomyoma . However , we finally made a diagnosis of this tumor as a smooth muscle tumor of uncertain malignant potential ( STUMP ) because of its huge size . Further information is required regarding the characteristics of ovarian smooth muscle tumor and the propriety to introduce uterine tumor histological criteria to ovarian tumors . OUTPUT:

resisting cell death

HoC_dynamic_1_shot105

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Overexpression and amplification of cyclin D1 were investigated by immunohistochemistry and differential polymerase chain reaction ( dPCR ) in 440 formalin-fixed primary breast carcinoma tissues . Overexpression of cyclin D1 was detected in 60% ( 263/440 ) and amplification of cyclin D1 was noted in 27% ( 119/440 ) of the primary breast carcinomas . Molecular analysis demonstrated that cyclin D1 was amplified in 30% ( 7/23 ) of the comedo DCIS , 22% ( 9/41 ) of the comedo DCIS and 32% ( 13/41 ) of the adjacent invasive ductal carcinomas , 30% ( 82/270 ) of the invasive ductal carcinomas , 27% ( 9/33 ) of the invasive lobular carcinomas , 19% ( 4/21 ) of the colloid carcinomas and 13% ( 2/15 ) of the medullary carcinomas . Cyclin D1 was amplified in 11% ( 2/19 ) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions . Our observation showed that cyclin D1 was strongly positive in 61% ( 14/23 ) of the comedo subtype , 61% ( 11/18 ) of the non-comedo subtype , 59% ( 24/41 ) of the comedo DCIS and 63% ( 26/41 ) of the adjacent invasive ductal carcinomas , 53% ( 10/19 ) of the non-comedo DCIS and 58% ( 11/19 ) of the adjacent invasive lesions , 58% ( 157/270 ) of the invasive ductal carcinomas , 73% ( 24/33 ) of the invasive lobular carcinomas , 52% ( 11/21 ) of the colloid carcinomas and 27% ( 4/15 ) of the medullary carcinomas . A significant association was observed between in situ components and adjacent invasive lesions for cyclin D1 expression ( p<0.05 ) and amplification ( p<0.05 ) . A significant relationship was noted between amplification of cyclin D1 and lymph node metastases ( p<0.05 ) but not with histological grade ( p>0.05 ) , estrogen receptor status ( p>0.05 ) and proliferation index ( Ki-67 and PCNA ) ( p>0.05 ) . However , overexpression of cyclin D1 was statistically associated with well differentiated tumors ( p<0.05 ) and estrogen receptor positivity ( p<0.05 ) . No relationship was seen with nodal status ( p>0.05 ) and proliferation index ( Ki-67 and PCNA ) ( p>0.05 ) . These observations suggest that tumors positive for cyclin D1 protein may have features of good prognosis but amplification of cyclin D1 gene could be an indicator of tumors with poor prognostic features . Although majority of the Malaysian patients belong to younger age group ( <50 years old ) , amplification and expression of cyclin D1 was not statistically associated with patient age ( p>0.05 ) . These observations indicate that amplification and up-regulation of cyclin D1 may be independent of patient age . Moreover , overexpression and amplification of cyclin D1 in preinvasive , preinvasive and adjacent invasive lesions , and invasive carcinomas suggest that the gene may play an important role in early and late stages of breast carcinogenesis . OUTPUT: sustaining proliferative signaling;activating invasion and metastasis INPUT: OBJECTIVE Ovarian carcinomas mostly appear as large cystic masses . However , the exact prevalence of cysts in epithelial ovarian cancer ( EOC ) has never been documented as well as the tumor factors that are related to the presence of cysts . Demonstrating the prevalence of cysts in EOC is essential for research focused on predictive and prognostic biomarkers in ovarian cyst fluid . STUDY DESIGN From 233 patients with primary EOC who underwent surgery , pathological data were collected from pathology reports . Univariate and multivariate logistic regression were used to analyze the relationship between the presence of cysts and other tumor characteristics . RESULTS Cysts in EOC were present in 83.7% of the patients and were mostly ( 61% ) multilocular . The most common histological subtypes ( serous , mucinous , endometrioid , clear cell ) contained cysts in more than 85% of the cases . In univariate regression analysis , early FIGO stage , low tumor grade and a large tumor size were significantly associated with the presence of cysts ( OR ( 95% CI)=5.312 ( 1.81-15.57 ) , 6.906 ( 2.31-20.66 ) and 1.169 ( 1.08-1.27 ) , respectively ) . In multivariate regression analysis , apart from tumor size , only tumor grade was independently associated with the presence of cysts ( adjusted OR ( 95% CI)=4.234 ( 1.36-13.22) ) . CONCLUSIONS The large majority of all EOCs contained cysts . Histological subtype , FIGO stage , tumor necrosis and age were not associated with the presence of cystic EOC . In contrast , tumor grade and tumor size were independently related to the presence of cystic EOC . This means that cystic EOCs represent a subgroup of larger and more well-differentiated tumors . The evident relationship between the presence of cysts and differentiation grade is interesting from a clinical point of view as grading is especially important for the prognosis and treatment of patients with stage I EOC . OUTPUT:

resisting cell death

HoC_dynamic_1_shot106

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Prostate cancer ( PCA ) is the most common invasive malignancy and the second leading cause of cancer-related death in males . The present study investigated the effects of fangchinoline ( Fan ) , an important compound in Stephania Tetradra S. Moore ( Fenfangji ) with pain-relieving , blood pressure-depressing , and antibiotic activities , on human PCA . It was found that Fan inhibited human prostate cancer cell lines ( PC3 ) cell proliferation in a dose- and time-dependent manner . Studies of cell-cycle progression showed that the anti-proliferative effect of Fan was associated with an increase in the G1/S phase of PC3 cells . Western blot results indicated that Fan-induced G1/S phase arrest was mediated through inhibition of cyclin-regulated signaling pathways . Fan induced p27 expression and inhibited cyclin D and proliferating cell nuclear antigen ( PCNA ) expression in PC3 cells . Increased exposure time to Fan caused apoptosis of PC3 cells , which was associated with up-regulation of pro-apoptotic proteins Bax and caspase 3 , and down-regulation of anti-apoptotic protein Bcl-2 . Furthermore , Fan had anti-tumorigenic activity in vivo , including reduction of tumor volume and pro-apoptotic and anti-proliferative effects in a PC3 nude mouse xenograft . Taking all this together , it can be concluded that Fan is an effective anti-proliferative agent that modulates cell growth regulators in prostate cancer cells . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: Colon cancer is a leading cause of morbidity and mortality in Western countries . Basic fibroblast growth factor ( bFGF ) was up-regulated in patients with colon cancer and was considered as a potential therapeutic target . In this study , we first demonstrated that a novel bFGF-binding peptide ( named P7 ) inhibited proliferation of several colon cancer cell lines including HT-29 , LoVo , and Caco2 cells stimulated by bFGF . Further investigations with HT-29 cells indicated that P7 arrested the cell cycle at the G0/G1 phase of bFGF-stimulated cells , reduced the levels of phospho-Erk1/Erk2 induced by bFGF , and caused significant changes in the expression of proteins related to proliferation , cell cycle , and cancer . Our results suggested that the bFGF-binding peptide has a potential antitumor effect on colon cancer . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot107

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "Intracellular pH ( pHi ) plays a critical role in the entry of cells into the DNA-synthesis phase of the cell cycle . Alterations in pHi may contribute to abnormal proliferative responses such as those seen in tumorigenic cells . We observed that alkaline stress leads to genomic transformation of Madin-Darby canine kidney ( MDCK ) cells . Transformed cells ( F cells ) form "" foci "" in culture , lack contact inhibition , and are able to migrate , typical characteristics of dedifferentiated tumorigenic cells . F cells exhibit spontaneous biorhythmicity . Rhythmic transmembrane Ca2+ flux activates plasma membrane K+ channels and Na+/H+ exchange . This leads to periodic changes of membrane voltage and pHi at about one cycle per minute . We conclude that endogenous oscillatory activity could be a trigger mechanism for DNA synthesis , proliferation , and abnormal growth of renal epithelial cells in culture ." OUTPUT: evading growth suppressors INPUT: In the present study , we investigated if the intracellular Cl(-) affects cell growth and cell cycle progression of androgen-independent prostate cancer PC3 cells . PC3 cells cultured in a medium containing 113 mM Cl(-) for 96 h grew up 9-fold in cell number , while PC3 cells cultured in an 8 mM-Cl(-)-containing culture medium showed complete arrest of cell growth even after culture for 96 h . Exposure of cells to the 8 mM-Cl(-) culture medium diminished phosphorylation levels of Rb and cdc2 , which are respectively key accelerators of transition from G(1) to S phase and G(2) to M phase in cell cycle progression . Culturing cells in the 8 mM-Cl(-)-containing culture medium upregulated the protein expression level of p21 ( a CDK inhibitor ) inhibiting transition of G(1) to S phase , and diminished the incorporation of 5-ethynyl-2'-deoxyuridine ( EdU ; a thymidine analogue ) into DNA . These results suggest that cells cultured in the low Cl(-) medium prolonged the duration of all phases of the cell cycle ( G(1) , S , and G(2)/M ) , thereby abolishing overall cell cycle progression . Effects of culturing cells in the low Cl(-) culture medium on cell cycle progression would be mediated via a change in the intracellular Cl(-) concentration ( [ Cl(-)](i) ) , since [ Cl(-)](i) was decreased under a low Cl(-) culture medium . To clarify this possibility , we studied effects of furosemide and bumetanide , Na+/K+/2Cl(-) cotransporter ( NKCC ) inhibitors , on proliferation of PC3 cells . Furosemide and bumetanide decreased [ Cl(-)](i) and cell growth of PC3 cells . These results suggest that a change in [ Cl(-)](i) would play a critical role in this growth mechanism . OUTPUT:

sustaining proliferative signaling;evading growth suppressors

HoC_dynamic_1_shot108

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression , and most human lung tumors express estrogen receptor β ( ERβ ) as well as aromatase . To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen , alone or in combination with the ER antagonist fulvestrant , ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone ( NNK ) along with daily supplements of androstenedione , the substrate for aromatase . Placebo , anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis . The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors ( mean = 0.5 ) compared with placebo ( mean = 4.6 , P &lt ; 0.001 ) , fulvestrant alone ( mean = 3.4 , P &lt ; 0.001 ) or anastrozole alone ( mean = 2.8 , P = 0.002 ) . A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups . Beginning antiestrogen treatment after NNK exposure , when preneoplastic lesions had already formed , also yielded maximum antitumor effects with the combination . Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs , whereas ERβ was found in both macrophages and tumor cells . Antiestrogens , especially in combination , effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention . An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens , beginning early in the carcinogenesis process . ERβ expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production . OUTPUT: sustaining proliferative signaling INPUT: Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents . We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a . Examination of normal lung tissue and tumors from 51 Gprc5a(+/+) ( adenoma incidence , 9.8% ; adenocarcinoma , 0% ) and 38 Gprc5a(-/-) mice ( adenoma , 63% ; adenocarcinoma , 21% ) revealed macrophage infiltration into lungs of 45% of the Gprc5a(-/-) mice and 8% of Gprc5a(+/+) mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice . Gprc5a(-/-) mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a(+/+) mice to stimulation of NF-kappaB activation by lipopolysaccharide in vivo . Studies with epithelial cells cultured from tracheas of Gprc5a(-/-) and Gprc5a(+/+) mice revealed that Gprc5a loss is associated with increased cell proliferation , resistance to cell death in suspension , and increased basal , tumor necrosis factor alpha-induced , and lipopolysaccharide-induced NF-kappaB activation , which were reversed partially in Gprc5a(-/-) adenocarcinoma cells by reexpression of Gprc5a . Compared with Gprc5a(+/+) cells , the Gprc5a(-/-) cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration . Silencing Gprc5a and the p65 subunit of NF-kappaB in Gprc5a(+/+) and Gprc5a(-/-) cells , respectively , reversed these effects . Thus , Gprc5a loss enhances NF-kappaB activation in lung epithelial cells , leading to increased autocrine and paracrine interactions , cell autonomy , and enhanced inflammation , which may synergize in the creation of a tumor-promoting microenvironment . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot109

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Cellular and clinical sensitivity to ionizing radiation ( IR ) is determined by DNA double-strand breaks ( DSB ) repair . Here , we investigate the molecular mechanism underlying the extreme response of a head and neck tumor case ( SKX ) to standard radiotherapy . METHODS Immunofluorescence ( IF ) was used for the assessment of DSB repair , Western blot and real-time PCR for protein and mRNA expression , respectively . RESULTS SKX cells exhibited a pronounced radiosensitivity associated with numerous residual γ-H2AX foci after IR . This was not associated with lacking canonical repair proteins . SKX cells did not express any ATM protein . Accordingly , immunoblotting revealed no ATM kinase activity toward substrates such as p-SMC1 , p-CHK2 and p-KAP1 . Sequencing of all 66 exons of ATM showed no mutation . ATM mRNA level was moderately reduced , which could be reverted by 5'-Aza-C treatment but without restoring protein levels . Importantly , we demonstrated a post-transcriptional regulation in SKX cells via 6-fold enhanced levels of miR-421 , which targets the 3'-UTR of ATM mRNA . Transfection of SKX cells with either anti-miR-421 inhibitor or a microRNA-insensitive ATM vector recovered ATM expression and abrogated the hyper-radiosensitivity . CONCLUSION This is the first report describing microRNA-mediated down-regulation of ATM leading to clinically manifest tumor radiosensitivity . OUTPUT: genomic instability and mutation INPUT: Treatment for glioblastoma multiforme includes the alkylating agent temozolomide combined with ionizing radiation . Persistent O6-guanine methylation by temozolomide in O6-methylguanine methyl transferase negative tumors causes cytotoxic lesions recognized by DNA mismatch repair , triggering apoptosis . Resistance ( intrinsic or acquired ) presents obstacles to successful temozolomide treatment , limiting drug efficacy and life expectancy . Two glioma cell lines , SNB19 and U373 , sensitive to temozolomide ( GI(50) values 36 and 68 microM , respectively ) were exposed to increasing temozolomide concentrations ( 1-100 microM ) . Variant cell lines ( SNB19VR , U373VR ) were generated that displayed acquired temozolomide resistance ( GI(50) values 280 and 289 microM , respectively ) . Cross-resistance to mitozolomide was observed in U373VR cells only . In clonogenic and MTT assays , methylguanine methyltransferase ( MGMT ) depletion using O6-benzylguanine sensitized U373VR cells to temozolomide , indicating the resistance mechanism involves MGMT re-expression . Indeed , Western blot analyses revealed MGMT protein in cell lysates . In SNB19VR cells , down-regulation of MSH6 message and protein expression may confer temozolomide tolerance . Inhibition of poly(ADP-ribose) polymerase-1 ( a key base excision repair ( BER ) enzyme ) partially restored sensitivity , and DNA repair gene arrays demonstrated up-regulation ( >5-fold ) of BER gene NTL1 in SNB19VR cells . In conclusion , we have developed two glioma cell lines whose distinct mechanisms of acquired resistance to temozolomide , involving expression of MGMT , or inactivation of DNA mismatch repair and recruitment of BER enzymes , are consistent with clinical observations . These cell lines provide valuable models for the development of strategies to combat temozolomide resistance . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot110

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Oncostatin M ( OSM ) , an interleukin-6 type cytokine , acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells . EGF , a mitogen for breast cells , signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis . Here we show paradoxically that EGF enhanced the OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells . This functional synergism was also seen with heregulin but not SCF , PDGF or IGF-1 , indicating that it was specific to EGF-related growth factors . Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3 . There was a similar association between the OSMRbeta and ErbB-2 . Furthermore , EGF unexpectedly induced tyrosine phosphorylation of gp130 . We show that OSM induced phosphorylation of STAT3 . Both OSM and EGF activated the p42/44 MAP kinases , but while the MEK inhibitor , PD98059 , ablated the OSM-induced inhibition , it only partially ablated the inhibitory effects of OSM plus EGF . Thus , we have demonstrated that the receptors and signalling pathways of two apparently unrelated growth factors were intimately linked , resulting in an unexpected biological effect . This provides a new mechanism for generating signalling diversity and has potential clinical implications in breast cancer . OUTPUT: sustaining proliferative signaling INPUT: MG132 , as a proteasome inhibitor , can induce apoptotic cell death through formation of reactive oxygen species ( ROS ) . In this study , we investigated the effects of MAPK ( MEK , JNK , and p38 ) inhibitors on MG132-treated A549 lung cancer cells in relation to cell growth , cell death , ROS , and glutathione ( GSH ) levels . Treatment with 10 microM MG132 inhibited the growth of A549 cells at 24 h . MG132 also induced apoptosis , which was accompanied by the loss of mitochondrial membrane potential ( MMP ; deltapsi(m) ) . ROS were not increased in MG132-treated A549 cells . MG132 increased GSH-depleted cell numbers and decreased GSH levels . MEK and JNK inhibitors did not strongly affect cell growth , cell death , ROS , and GSH levels in MG132-treated A549 cells . In contrast , p38 inhibitor reduced cell growth inhibition , apoptosis , and MMP ( deltapsi(m) ) loss by MG132 . However , p38 inhibitor did not change ROS level and GSH content . In conclusion , MG132 inhibited the growth of A549 cells via apoptosis without formation of ROS . Treatment with p38 inhibitor rescued some cells from MG132-induced apotposis , which was not affected by ROS and GSH level changes . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot111

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks ( DSBs ) . DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis . Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact . Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer . METHODS Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide ( EC ) treatment . Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy . RESULTS EC treatment induced nuclear foci of gammaH2AX , conjugated ubiquitin , and Rad51 in a substantial amount of cases . In contrast , BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases . The presence of BRCA1- , gammaH2AX- , or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy . DNA damage response ( DDR ) competence was further evaluated by considering all four repair indicators together . A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not . CONCLUSIONS High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy . Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity , and merits further studying into its usefulness in exclusion of non-responder patients . OUTPUT: genomic instability and mutation INPUT: A novel camptothecin derivative ( TLC388 ) with higher efficacy and reduced toxicity has been synthesized and tested as a novel chemoradiosensitizing agent . This study investigated the mechanisms of the chemoradiosensitizing effects of TLC388 on H23 human non-small cell lung cancer ( NSCLC ) cells . Using the TUNEL assay , a significantly higher percentage of apoptotic cells was observed in the group treated with TLC388 plus X-ray radiation than those in groups treated with drug or radiation alone . The sensitizer enhancement ratio ( SER ) was 1.91 . Apoptosis increased with drug concentration and radiation dose , exhibiting dose-dependent pattern . The results suggested that apoptosis could be a main mode of cell death that might underlie the increased chemoradio-sensitization of TLC388 . Treatment with 30 nM of TLC388 plus 4 Gy X-ray also produced up to 42% of necrotic cells that were measured by trypan blue exclusion assay , but with TLC388 alone or 4 Gy radiation alone 9.8% or 11.1% necrotic cells were detected , respectively . An immunofluorescent staining method was employed to determine the levels of gamma-H2AX ( phosphorylated H2AX , a variant of the H2A protein family , which is a component of the histone octomer in nucleosomes and is phosphorylated by kinases like ATM and ATR in the PI3K pathway , as the first step in recruiting and localizing DNA repair proteins ) as a molecular biomarker of DNA double strand breaks ( DSBs ) in cells treated with TLC388 +/-radiation , or radiation alone . The formation of gamma-H2AX foci was observed after TLC388 or radiation exposure and when the cells were treated with 30 nM TLC388 plus radiation at a dose of 2 Gy , the percentage of cells containing gamma-H2AX foci increased significantly . Even more interesting , a markedly higher percentage ( 65.4% ) of mitotic cells displayed gamma-H2AX foci after treatment with 30 nM TLC388 plus 0.5 Gy radiation , compared to only 5.9% or 26.1% of the M-phase cells treated with 30 nM TLC388 alone or 0.5 Gy radiation alone , respectively . It is suggested that mitotic cells become very sensitive to the production of DSBs after TLC388-radiation combined treatment and the formation of DSBs is strongly suggested to lead to the induction of apoptosis at doses lower than 4 Gy and to some necrosis at doses of 4 Gy or above . TLC388 enhances the production of DSBs and inhibits their repair , which contributes to the elucidation of the mechanisms of chemoradiosensitization of TLC388 and its development as a novel chemoradiosensitizing drug for improved radiotherapy . OUTPUT:

resisting cell death;genomic instability and mutation

HoC_dynamic_1_shot112

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells . In this study , we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma , documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes ( CTL). miR-210 was induced in hypoxic zones of human tumor tissues . Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis , independent of tumor cell recognition and CTL reactivity . A comprehensive approach using transcriptome analysis , argonaute protein immunoprecipitation , and luciferase reporter assay revealed that the genes PTPN1 , HOXA1 , and TP53I11 were miR-210 target genes regulated in hypoxic cells . In support of their primary importance in mediating the immunosuppressive effects of miR-210 , coordinate silencing of PTPN1 , HOXA1 , and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis . Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis , by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve . OUTPUT: avoiding immune destruction;activating invasion and metastasis INPUT: The hypoxic tumor microenvironment is associated with malignant progression and poor treatment response . The glucose transporter Glut-1 is a prognostic factor and putative hypoxia marker . So far , studies of Glut-1 in cancer have utilized conventional immunohistochemical analysis in a series of individual biopsy or surgical specimens . Tissue microarrays , however , provide a rapid , inexpensive means of profiling biomarker expression . To evaluate hypoxia markers , tissue cores must show the architectural features of hypoxia ; i.e. viable tissue surrounding necrotic regions . Glut-1 may be a useful biomarker to validate tissue microarrays for use in studies of hypoxia-regulated genes in cancer . In this study , we carried out immunohistochemical detection of Glut-1 protein in many tumor and normal tissue types in a range of tissue microarrays . Glut-1 was frequently found in peri-necrotic regions , occurring in 9/34 lymphomas , 6/12 melanomas , and 5/16 glioblastomas ; and in 43/54 lung , 22/84 colon , and 23/60 ovarian tumors . Expression was rare in breast ( 6/40 ) and prostate ( 1/57 ) tumors , and in normal tissue , was restricted to spleen , tongue , and CNS endothelium . In conclusion , tissue microarrays enable the observation of Glut-1 expression in peri-necrotic regions , which may be linked to hypoxia , and reflect previous studies showing differential Glut-1 expression across tumor types and non-malignant tissue . OUTPUT:

resisting cell death

HoC_dynamic_1_shot113

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION A subpopulation of cancer cells , tumor-initiating cells , is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy . The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins , as well as a reduced propensity to undergo apoptosis or senescence . METHODS To test this hypothesis , we isolated CD24-/low/CD44+ tumor-initiating cells ( as mammospheres ) from MCF-7 breast cancer cells grown in adherent monolayer culture , and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells . Single and double-strand break repair was measured by single-cell gel electrophoresis . The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci . Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular beta-galactosidase activity . We employed the telomeric repeat amplification protocol to quantify telomerase activity . Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis . RESULTS Our data demonstrate that in comparison to the bulk population of MCF-7 cells ( predominantly CD24+/CD44+ ) , the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells , including a reduced level of reactive oxygen species , a more active DNA single-strand break repair ( SSBR ) pathway , possibly due to a higher level of expression of the key SSBR protein , human AP endonuclease 1 ( Ape1 ) , and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression . No significant difference was seen in the rates of double-strand break repair ( DSBR ) between the two cell types , but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation . CONCLUSIONS Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway . Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis , consideration of senescence pathways may play a role in targeting stem cells from such tumors . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;resisting cell death INPUT: OBJECTIVE Although downregulation of neural cell adhesion molecule ( NCAM ) has been correlated with poor prognosis in colorectal cancer ( CRC ) , it is also possible that colon cancer spreading comes from reducing tumor cell adhesion through NCAM polysialylation , as occurs in lung carcinoma or Wilms ' tumor . METHODS To prove this hypothesis , we have performed a prospective study on tumor and control specimens from 39 CRC patients , which were immunostained for NCAM and PSA ( polysialic acid ) expression . RESULTS Tumor versus control expression of NCAM and PSA epitopes in tissue specimens , as well as correlation between tumor expression and clinicopathological features , were statistically analyzed . Results showed a low constitutive expression of NCAM and PSA ( PSA-NCAM ) in control tissue , which reached a statistically significant increase in the tumor tissue . Likewise , the presence and number of lymph node metastases at surgery were correlated with NCAM expression and PSA/NCAM coexpression . CONCLUSIONS These data highlight the importance of taking into account PSA-associated epitopes when dealing with NCAM cell expression studies in tumor development and progression . The analysis of PSA and NCAM expression in CRC suggests a new way , other than downregulation of NCAM , in order to escape contact inhibition and promote cell tumor spreading in colorectal cancer . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot114

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC₅₀ value of 5 μg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 μg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation . OUTPUT: evading growth suppressors;resisting cell death INPUT: In order to increase the permeability of cell membranes for low doses of cytostatic drugs , two bioelectrochemical methods have been compared : ( a ) electric pore formation in the plasma membranes by single electric impulses ( electroporation ) , and ( b ) reordering of membrane structure by alternating currents ( capacitively coupled ) . These treatments were applied to human leukemic K-562 cells and human lymphoma U-937 cells , yielding apoptotic and necrotic effects , determined by flow cytometry . Additional cell death occurs after exposure to light irradiation at wavelengths lambda &gt ; 600 nm , of cells which were electroporated and had incorporated actinomycin-C or daunomycin ( daunorubicin ) . It is observed that drug uptake after an exponentially decaying electroporation pulse of the initial field strength Eo=1.4 kV/cm and pulse time constants in the time range 0.5-3 ms is faster than during PEMF-treatment , i.e. , application of an alternating current of 16 kHz , voltage U<100 V , I=55 mA , and exposure time 20 min . However , at the low a.c. voltage of this treatment , more apoptotic and necrotic cells are produced as compared to the electroporation treatment with one exponentially decaying voltage pulse . Thus , additional photodynamic action appears to be more effective than solely drugs and electroporation as applied in clinical electrochemotherapy , and more effective than the noninvasive pulsed electromagnetic fields ( PEMFs ) , for cancer cells in general and animals bearing tumors in particular . OUTPUT:

resisting cell death

HoC_dynamic_1_shot115

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: PURPOSE Pyruvate kinase isoenzyme M2 ( PKM2 ) is a key enzyme in aerobic glycolysis ; inhibition of PKM2 leads to the tumor growth inhibition . In this study , the effects of combined treatment with cisplatin ( DDP ) and a plasmid that expresses a short hairpin RNA ( shRNA ) targeting PKM2 on the growth of human A549 xenograft lung cancer model were investigated . METHODS The expression of PKM2 in A549 cells was determined by immunofluorescence . PKM2 expression levels were evaluated by Western blot analysis . In a human A549 lung cancer xenograft model , the effects of treatment with shRNA , with or without cisplatin , on tumor volume were determined . Apoptosis and cell proliferation status were examined to determine the mechanisms of tumor growth inhibition . RESULTS Expression of shRNA targeting PKM2 resulted in inhibition of PKM2 expression in A549 cells . In the lung cancer xenograft model , average tumor volume in the group treated with both cisplatin and shRNA was statistically lower than those of other groups ( P &lt ; 0.05 ) . The levels of apoptotic cells were significantly higher in samples from animals in the combined treatment group than those from untreated animals ( P &lt ; 0.05 ) . The cell proliferation rate , as determined by counting cells labeled with an anti-phospho-histone H3 , a marker for mitosis , was lower in samples from animals treated with both cisplatin and shRNA than in samples from other groups ( P &lt ; 0.05 ) . CONCLUSIONS Use of RNA interfering ( RNAi ) targeting PKM2 significantly inhibited tumor growth when combined with cisplatin in a human A549 lung cancer xenograft model . The enhanced antitumor activity of the combined treatment compared to treatment with shRNA alone may result in part from increased induction of apoptosis and augmented inhibition of cancer cell proliferation . OUTPUT: resisting cell death INPUT: Tumor aerobic glycolysis , or the Warburg effect , plays important roles in tumor survival , growth , and metastasis . Pyruvate kinase isoenzyme M2 ( PKM2 ) is a key enzyme that regulates aerobic glycolysis in tumor cells . Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and , in particular , as a potential target for cancer therapy . We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro . We observed that the shRNA can significantly downregulate the expression level of PKM2 . The decrease of PKM2 resulted in a decrease in ATP synthesis , which caused intracellular accumulation of docetaxel . Furthermore , the combination of pshRNA-pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro . Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy . In particular , the targeting of PKM2 could , to some extent , be a new way of reversing chemotherapy resistance to cancer therapy . OUTPUT:

cellular energetics

HoC_dynamic_1_shot116

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A 39-year-old male without contributory medical history had sustained progressive double vision , ptosis , and trigeminal pain for 2 weeks . Physical examination revealed total ophthalmoplegia and visual field defect with normal blood examination and chest radiography . Cranial computed tomography revealed a hyperdense mass in the left frontotemporal fossae with bony erosion . Magnetic resonance imaging confirmed a broad-based , intensely enhanced extraaxial tumor of 4x4x4 cm diameter with dural tail sign . Cerebral angiography demonstrated insignificant blood supply both from the internal carotid and middle meningeal arteries . Nearly total tumor resection was achieved via orbitofrontotemporal craniotomy . Intraoperative findings revealed the extraaxial tumor with broad attachment to the dura mater and invasion to the optic and oculomotor nerves . Histological examination revealed hypercellular tumor with significant cell atypism , mitotic activity , and focal necrosis . Immunohistochemical staining was positive for AE1/3 and c-kit , but negative for glial fibrillary acidic protein . Systemic examination performed postoperatively revealed a thymic tumor without additional remote lesions . The final diagnosis was metastatic brain tumor from thymic carcinoma . Rapid progression of neurological impairment inconsistent with a benign extraaxial tumor needs prompt surgical intervention . OUTPUT: resisting cell death INPUT: A 33-year-old man presented with pain and palsy of the leg in 2008 for treatment of hepatocellular carcinoma with huge distant metastases . The patient's tumors had slowly enlarged despite several treatments . Oral administration of sorafenib at 800 mg/day with careful observation was commenced in 2009 . Laboratory investigations on day 7 showed massive tumor lysis . An abdominal CT showed multiple low density areas and tumor markers decreased , indicating extended tumor necrosis . In conclusion , clinicians should bear in mind not only the published adverse effects , but also massive tumor lysis , when treating patients with large tumor burden by sorafenib . OUTPUT:

resisting cell death

HoC_dynamic_1_shot117

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "Caveolin-1 ( -/- ) null stromal cells are a novel genetic model for cancer-associated fibroblasts and myofibroblasts . Here , we used an unbiased informatics analysis of transcriptional gene profiling to show that Cav-1 ( -/- ) bone-marrow derived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers . More specifically , the transcriptional profiles of Cav-1 ( -/- ) stromal cells were most closely related to the primary tumor stroma of breast cancer patients that had undergone lymph-node ( LN ) metastasis . This is consistent with previous morphological data demonstrating that a loss of stromal Cav-1 protein ( by immuno-histochemical staining in the fibroblast compartment ) is significantly associated with increased LN-metastasis . We also provide evidence that the tumor stroma of human breast cancers shows a transcriptional shift towards oxidative stress , DNA damage/repair , inflammation , hypoxia , and aerobic glycolysis , consistent with the "" Reverse Warburg Effect "" . Finally , the tumor stroma of "" metastasis-prone "" breast cancer patients was most closely related to the transcriptional profiles derived from the brains of patients with Alzheimer's disease . This suggests that certain fundamental biological processes are common to both an activated tumor stroma and neuro-degenerative stress . These processes may include oxidative stress , NO over-production ( peroxynitrite formation ) , inflammation , hypoxia , and mitochondrial dysfunction , which are thought to occur in Alzheimer?s disease pathology . Thus , a loss of Cav-1 expression in cancer-associated myofibroblasts may be a protein biomarker for oxidative stress , aerobic glycolysis , and inflammation , driving the "" Reverse Warburg Effect "" in the tumor micro-environment and cancer cell metastasis ." OUTPUT: cellular energetics;genomic instability and mutation;tumor promoting inflammation INPUT: "Cav-1 ( -/- ) deficient stromal cells are a new genetic model for myofibroblasts and cancer-associated fibroblasts . Using an unbiased informatics analysis of the transcriptional profile of Cav-1 ( -/- ) deficient mesenchymal stromal cells , we have now identified many of the major signaling pathways that are activated by a loss of Cav-1 , under conditions of metabolic restriction ( with low glucose media ) . Our informatics analysis suggests that a loss of Cav-1 induces oxidative stress , which mimics a constitutive pseudo-hypoxic state , leading to ( 1 ) aerobic glycolysis and ( 2 ) inflammation in the tumor stromal microenvironment . This occurs via the activation of two major transcription factors , namely HIF ( aerobic glycolysis ) and NFκB ( inflammation ) in Cav-1 ( -/- ) stromal fibroblastic cells . Experimentally , we show that Cav-1 deficient stromal cells may possess defective mitochondria , due to the over-production of nitric oxide ( NO ) , resulting in the tyrosine nitration of the mitochondrial respiratory chain components ( such as complex I ) . Elevated levels of nitro-tyrosine were observed both in Cav-1 ( -/- ) stromal cells , and via acute knock-down with siRNA targeting Cav-1 . Finally , metabolic restriction with mitochondrial ( complex I ) and glycolysis inhibitors was synthetically lethal with a Cav-1 ( -/- ) deficiency in mice . As such , Cav-1 deficient mice show a dramatically reduced mitochondrial reserve capacity . Thus , a mitochondrial defect in Cav-1 deficient stromal cells could drive oxidative stress , leading to aerobic glycolysis , and inflammation , in the tumor microenvironment . These stromal alterations may underlie the molecular basis of the "" reverse Warburg effect "" , and could provide the key to targeted anti-cancer therapies using metabolic inhibitors . In direct support of these findings , the transcriptional profile of Cav-1 ( -/- ) stromal cells overlaps significantly with Alzheimer disease , which is characterized by oxidative stress , NO over-production ( peroxynitrite formation ) , inflammation , hypoxia and mitochondrial dysfunction . We conclude that Cav-1 ( -/- ) deficient mice are a new whole-body animal model for an activated lethal tumor microenvironment , i.e. , "" tumor stroma "" without the tumor . Since Cav-1 ( -/- ) mice are also an established animal model for profibrotic disease , our current results may have implications for understanding the pathogenesis of scleroderma ( systemic sclerosis ) and pulmonary fibrosis , which are also related to abnormal mesenchymal stem cell function ." OUTPUT:

tumor promoting inflammation;cellular energetics

HoC_dynamic_1_shot118

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Amplification of the HER-2 ( c-erbB-2 ) gene and overexpression of the p185HER-2 gene product is found in approximately one-third of primary human breast and ovarian cancers and is associated with a poor clinical outcome of early relapse and death . The HER-2 gene encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity . Wild-type human HER-2 has been shown to act as a potent oncogene when over-expressed in mouse fibroblasts . Recent data suggest that the mechanism by which HER-2 mediates transformation requires the interaction of the epidermal growth factor ( EGF ) receptor . To test whether overexpression of normal human HER-2 can transform cells independently of the EGF receptor , we have introduced multiple copies of HER-2 into the EGF receptor-negative cell line , NR6 , and have performed assays for both transformation and tumorigenicity . Engineered NR6 cells that overexpress the HER-2 gene product display a highly transformed and tumorigenic phenotype as compared with control cells . Additionally , a monoclonal antibody to the extracellular domain of the HER-2 receptor is able to inhibit the proliferation of the overexpressing cells in vitro as well as tumor growth in vivo . This study provides clear evidence that HER-2-mediated transformation can be achieved independently of the EGF receptor . OUTPUT: sustaining proliferative signaling INPUT: Overexpression/amplification of human epidermal growth factor receptor ( HER)2/neu ( erbB-2 ) oncogene plays a causal role in carcinogenesis and correlates with a poor clinical prognosis . However , little is known about HER2 in gastric cancer . In this study , we explored the pharmacological activities of natural triterpenoid corosolic acid ( CRA ) in HER2 signaling and its role in gastric cancer development and progression . In this study , CRA dramatically inhibited HER2 expression in a dose- and time-dependent manner , effectively inhibited cell proliferation , and induced G(0)/G(1) arrest through the induction of p27(kip1) and cyclin D(1) down-regulation . CRA exposure enhanced apoptotic cell death , as confirmed by caspase-3 and poly ( ADP-ribose ) polymerase cleavage activities . CRA inhibited signaling pathways downstream of HER2 , including phospho-proteins such as Akt and Erk . In addition , CRA combined with adriamycin and 5-fluorouracil enhanced this growth inhibition , but not with docetaxel and paclitaxel . These findings demonstrate that CRA suppresses HER2 expression , which in turn promotes cell cycle arrest and apoptotic cell death of gastric cancer cells , providing a rationale for future clinical trials of CRA in the treatment of HER2-positive gastric cancers . OUTPUT:

evading growth suppressors;sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot119

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION HER2 and estrogen receptor ( ER ) are important in breast cancer and are therapeutic targets of trastuzumab ( Herceptin ) and tamoxifen , respectively . Retinoids inhibit breast cancer growth , and modulate signaling by HER2 and ER . We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects . METHODS The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture , BT474 and SKBR3 . Assays of proliferation , apoptosis , differentiation , cell cycle distribution , and receptor signaling were performed . RESULTS In HER2-overexpressing/ER-positive BT474 cells , combining all-trans retinoic acid ( atRA ) with tamoxifen or trastuzumab synergistically inhibited cell growth , and altered cell differentiation and cell cycle . Only atRA/trastuzumab-containing combinations induced apoptosis . BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids ( atRA , 9-cis-retinoic acid , 13-cis-retinoic acid , or N-(4-hydroxyphenyl) retinamide ( fenretinide ) ( 4-HPR) ) combined with trastuzumab . In BT474 cells , none of the single agents except 4-HPR induced apoptosis , but again combinations of each retinoid with trastuzumab did induce apoptosis . In contrast , the single retinoid agents did cause apoptosis in SKBR3 cells ; this was only modestly enhanced by addition of trastuzumab . The retinoid drug combinations altered signaling by HER2 and ER . Retinoids were inactive in trastuzumab-resistant BT474 cells . CONCLUSIONS Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells . Treatment with such combinations may have benefit for breast cancer patients . OUTPUT: sustaining proliferative signaling;resisting cell death INPUT: INTRODUCTION Anterior-gradient 2 ( AGR2 ) is an estrogen-responsive secreted protein . Its upregulation has been well documented in a number of cancers , particularly breast cancer , for which mixed data exist on the prognostic implications of AGR2 expression . Although emerging evidence indicates that AGR2 is associated with poor prognosis , its function and impact on cancer-relevant pathways have not been elucidated in breast cancer . METHODS To investigate the biologic role of AGR2 in breast cancer , AGR2 was transiently knocked down , by using siRNA , in T47 D and ZR-75-1 ( estrogen receptor-alpha ( ER)-positive ) and MDA-MB-231 and SK-BR-3 ( ER-negative ) human breast cancer cell lines . The impact of silencing AGR2 was evaluated in both anchorage-dependent and anchorage-independent growth ( soft agar , spheroid ) assays . Cell-cycle profiles in ER-positive cell lines were determined with BrdU incorporation , and cell death was measured with Annexin V , JC-1 , and F7-26 staining . After transiently silencing AGR2 or stimulating with recombinant AGR2 , modulation of key regulators of growth and survival pathways was assessed with Western blot . Combination studies of AGR2 knockdown with the antiestrogens tamoxifen and fulvestrant were carried out and assessed at the level of anchorage-dependent growth inhibition and target modulation ( cyclin D1 , ER ) . RESULTS AGR2 knockdown inhibited growth in anchorage-dependent and anchorage-independent assays , with a more-pronounced effect in ER-positive cell lines . Cyclin D1 levels and BrdU incorporation were reduced with AGR2 knockdown . Conversely , cyclin D1 was induced with recombinant AGR2 . AGR2 knockdown induced cell death in ZR-75-1 and T47 D cells , and also downregulated survivin and c-Myc . Evidence of AGR2-ER crosstalk was demonstrated by a reduction of ER at the protein level after transiently silencing AGR2 . AGR2 knockdown in combination with fulvestrant or tamoxifen did not preclude the efficacy of the antiestrogens , but enhanced it . In addition , p-Src , implicated in tamoxifen resistance , was downregulated with AGR2 knockdown . CONCLUSIONS Transiently silencing AGR2 in ER-positive breast cancer cell lines inhibited cell growth and cell-cycle progression and induced cell death . Breast cancer drivers ( ER and cyclin D1 ) as well as cancer-signaling nodes ( pSrc , c-Myc , and survivin ) were demonstrated to be downstream of AGR2 . Collectively , the data presented support the utility of anti-AGR2 therapy in ER-positive breast cancers because of its impact on cancer-relevant pathways . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot120

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence . Consistent with this role , p21 is a downstream target of several tumour suppressors and oncogenes , and it is downregulated in the majority of tumours , including breast cancer . Here , we report that protein arginine methyltransferase 6 ( PRMT6 ) , a type I PRMT known to act as a transcriptional cofactor , directly represses the p21 promoter . PRMT6 knock-down ( KD ) results in a p21 derepression in breast cancer cells , which is p53-independent , and leads to cell cycle arrest , cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency ( SCID ) mice for all the cancer lines examined . We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence , and it restores their ability to grow on soft agar . We conclude that PRMT6 acts as an oncogene in breast cancer cells , promoting growth and preventing senescence , making it an attractive target for cancer therapy . OUTPUT: enabling replicative immortality;sustaining proliferative signaling INPUT: The deregulation of Met/hepatocyte growth factor ( HGF ) receptor tyrosine kinase signaling constitutes a common event in colorectal cancers . However , the physiopathological functions of such a deregulation remain poorly understood . In the present study , we investigated the role of the deregulation of Met receptor in the neoplastic transformation of intestinal epithelial cells . To do so , the normal , well-established and characterized rat intestinal epithelial IEC-6 cells were transduced with a retrovirus carrying the oncogenic constitutive active form of Met receptor , Tpr-Met . Herein , we show that compared with control IEC-6 cells , Tpr-Met-IEC-6 cells exhibit enhanced proliferation , loss of growth-contact inhibition , cell morphological alterations , actin cytoskeletal reorganization , loss of E-cadherin expression and anchorage-independent growth . Moreover , Tpr-Met-IEC-6 cells are conferred the capacity to produce the proangiogenic factor VEGF and to reduce the potent antiangiogenic factor thrombospondin-1 . Of significance , Tpr-Met-IEC-6 cells are endowed with the ability to elicit angiogenic responses and to form tumors and metastases in vivo . Hence , our study demonstrates for the first time that the sole oncogenic engagement of Met receptor in normal intestinal epithelial cells is sufficient to induce a wide array of cancerous biological processes that are fundamental to the initiation and malignant progression of colorectal cancers . OUTPUT:

evading growth suppressors;inducing angiogenesis

HoC_dynamic_1_shot121

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Several studies have indicated that the cell-surface expressed nucleolin is implicated in tumorigenesis and angiogenesis , and represents an important target for cancer therapy . Here we show that treatment of rhabdoid tumor derived G401 cells with a nucleolin antagonist , the HB-19 pseudopeptide , could restore contact inhibition , impair anchorage-independent growth , and suppress tumor development in nude mice . G401 cells grow without contact inhibition , which is an in vitro characteristic property of malignant tumor cells . At concentrations of HB-19 that does not affect cell viability and multiplication index , there is restoration of contact inhibition thus suggesting that HB-19 treatment causes reversion of the malignant phenotype . Accordingly , HB-19 pretreated G401 cells lose the capacity to form colonies in soft agar . When assayed for tumorigenicity in nude mice , only 50% of mice injected with HB-19 pretreated G401 cells developed tumors with the mean tumor weight of 0.32 g , compared to 100% of mice injected with control G401 cells with the mean tumor weight of 2.36 g . Interestingly , the restoration of contact inhibition in HB-19 treated G401 cells is concomitant with marked reduction of transcripts coding the Wilms ' tumor 1 gene , matrix metalloproteinase-2 , epithelial isoform of CD44 , and vascular endothelial growth factor , whereas no apparent modification is detected for transcripts coding the proto-oncogene c-Myc , anti-apoptotic Bcl-2 , pro-apoptotic Bax , tissue inhibitor of metalloproteinase TIMP-1 , angiogenesis inhibitor TSP-1 , and growth factor Midkine . These findings indicate that the molecular mechanism of action of HB-19 on such highly malignant rhabdoid tumor cells is associated with a selective inhibitory effect on the expression of genes implicated in tumorigenesis and angiogenesis . OUTPUT: evading growth suppressors INPUT: BACKGROUND The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis . By using a specific antagonist that binds the C-terminal tail of nucleolin , the HB-19 pseudopeptide , we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity . METHODS The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model . Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days . In parallel , the molecular basis for the action of HB-19 was investigated on a melanoma cell line ( called TIII ) derived from a cutaneous nodule of a RET mouse . RESULTS HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors , several-months delay in the incidence of large tumors , a lower frequency of cutaneous nodules , and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue . Moreover , microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls . Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition , impair anchorage-independent growth , and reduce their tumorigenic potential in mice . Moreover , HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9 , and tumor necrosis factor-alpha in the TIII cells and in melanoma tumors of RET mice . CONCLUSIONS Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice , it delayed for several months the onset and frequency of cutaneous tumors , and exerted a significant inhibitory effect on visceral metastasis . Consequently , HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma . OUTPUT:

inducing angiogenesis;evading growth suppressors;activating invasion and metastasis

HoC_dynamic_1_shot122

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Androgens and the androgen receptor ( AR ) play important roles in the development of male urogenital organs . We previously found that mice with total AR knockout ( ARKO ) and epithelial ARKO failed to develop normal prostate with loss of differentiation . We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate . However , AR roles of stromal fibroblasts in prostate development remain unclear . METHODS To further probe the stromal fibroblast AR roles in prostate development , we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts ( FSP-ARKO ) . We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development . RESULTS The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation , increased apoptosis , and decreased collagen composition . Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors . To further confirm these in vivo findings , we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells , as well as decrease of some stromal growth factors . CONCLUSIONS Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate , but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: BACKGROUND The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy . Unlike breast cancer , the prognostic role of the human epidermal growth factor receptor-2 ( HER-2 ) in ovarian carcinoma remains controversial . METHODS The aim of this preclinical study was to further characterise the biological , molecular and cellular effects of trastuzumab ( Herceptin ) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo . RESULTS In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2 . This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue ( PTEN ) , mitogen-activated protein kinase and AKT , and the total level of p27(kip) . Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation , suggesting a specific inhibition of the protein phosphatase function of PTEN . Moreover , trastuzumab induced the upregulation of RhoB . These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition . RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects . RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model . In vivo examinations have shown that these changes are also associated with the restoration of structural , morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model . CONCLUSION These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression . These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer . OUTPUT:

sustaining proliferative signaling;evading growth suppressors

HoC_dynamic_1_shot123

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases . OUTPUT: resisting cell death;avoiding immune destruction INPUT: INTRODUCTION The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug . Several studies have shown that nelfinavir induces cell cycle arrest , endoplasmic reticulum stress , autophagy , and apoptosis in cancer cells . In the present article , the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated . METHODS The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7 , T47 D , MDA-MB-453 , and MDA-MB-435 were tested by analysing their influence on cell viability ( via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay ) , apoptosis ( annexin binding , poly(ADP-ribose) polymerase cleavage ) , autophagy ( autophagy marker light chain 3B expression ) , endoplasmic reticulum stress ( binding protein and activating transcription factor 3 expression ) , and the occurrence of oxidative stress ( intracellular glutathione level ) . RESULTS Nelfinavir induced apoptosis in all four breast cancer cell lines tested , although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines . The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 μg/ml to 6 μg/ml when combined with tamoxifen . At a concentration of 6 μg/ml , tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein ( BiP ) upregulation ( MCF7 , T47D ) , and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation ( MDA-MB-453 ) . Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study ( 6 μg/ml ) , we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32% , suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir . CONCLUSIONS The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells . Moreover , the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells , suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours . We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot124

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Liver cancer , predominantly hepatocellular carcinoma ( HCC ) , represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation . Due to dismal prognosis and limited therapeutic intervention , chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC . Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties . We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine ( DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 ( Nrf2)-mediated antioxidant mechanisms . Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB ( NF-κB)-regulated inflammatory pathway , our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion ( PE ) during DENA-induced rat hepatocarcinogenesis . Rats were administered with PE ( 1 or 10 g/kg ) 4 weeks before and 18 weeks following DENA initiation . There was a significant increase in hepatic expressions of inducible nitric oxide synthase , 3-nitrotyrosine , heat shock protein 70 and 90 , cyclooxygenase-2 and NF-κB in DENA-exposed rat livers . PE dose-dependently suppressed all aforementioned elevated inflammatory markers . A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography . Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-κB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis . Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits , namely , Nrf2-mediated redox signaling and NF-κB-regulated inflammatory pathway , by pomegranate phytoconstituents to achieve chemoprevention of HCC . OUTPUT: tumor promoting inflammation INPUT: AIMS Cisplatin-induced nephrotoxicity is associated with increased oxidative stress and inflammatory cytokines in the kidney . Epigallocatechin-3-gallate ( EGCG ) has anti-oxidant , anti-inflammatory , and anti-tumorigenic properties . In this study , we investigated the effects of EGCG on cisplatin-induced nephrotoxicity and potential mechanisms by which it enhances antioxidant activities and resolves inflammation after EGCG treatment during cisplatin-induced nephrotoxicity . MAIN METHODS Twenty-eight rats were divided into four groups as control ( group 1 ; no treatment ; n=7 ) , EGCG ( group 2 ; n=7 ) , cisplatin ( group 3 ; n=7 ) or cisplatin and EGCG ( group 4 ; n=7 ) . After 2 days of EGCG treatment at a dose of l00 mg/kg BW , rats were treated with a single i.p. injection of cisplatin ( 7 mg/kg BW ) . On day 12 ( 10days after the cisplatin treatment ) , all rats were sacrificed by cervical dislocation . The level of protein was examined by Western blotting . KEY FINDINGS Cisplatin caused a significant decrease in the expression nuclear levels of NF-E2-related factor-2 ( Nrf2 ) , heme oxygenase-1(HO-1) , and an increase in the levels of nuclear factor-kappa B ( NF-kappaB p65 ) and 4-hydroxynonenal ( HNE ) an oxidative stress marker . EGCG supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing levels of Nrf-2 and HO-1 , and decreasing levels of NF-kappaB and HNE . Renal activities of antioxidant enzymes ( catalase , superoxide dismutase , glutathione peroxidase ) and glutathione were significantly lower in cisplatin-treated rats compared with control rats , and EGCG treatment significantly increased the activities of antioxidant enzymes and glutathione ( P<0.001 ) . SIGNIFICANCE The results suggest that Nrf2/HO-1 signaling pathway may be the primary target for prevention of cisplatin-induced nephrotoxicity by EGCG , and that reduces it inflammation by inhibiting NF-kappaB . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot125

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The DNA mismatch repair ( MMR ) pathway corrects specific types of DNA replication errors that affect microsatellites and thus is critical for maintaining genomic integrity . The genes of the MMR pathway are highly conserved across different organisms . Likewise , defective MMR function universally results in microsatellite instability ( MSI ) which is a hallmark of certain types of cancer associated with the Mendelian disorder hereditary nonpolyposis colorectal cancer . ( Lynch syndrome ) . To identify previously unrecognized deleted genes or loci that can lead to MSI , we developed a functional genomics screen utilizing a plasmid containing a microsatellite sequence that is a host spot for MSI mutations and the comprehensive homozygous diploid deletion mutant resource for Saccharomyces cerevisiae . This pool represents a collection of non-essential homozygous yeast diploid ( 2N ) mutants in which there are deletions for over four thousand yeast open reading frames ( ORFs ) . From our screen , we identified a deletion mutant strain of the PAU24 gene that leads to MSI . In a series of validation experiments , we determined that this PAU24 mutant strain had an increased MSI-specific mutation rate in comparison to the original background wildtype strain , other deletion mutants and comparable to a MMR mutant involving the MLH1 gene . Likewise , in yeast strains with a deletion of PAU24 , we identified specific de novo indel mutations that occurred within the targeted microsatellite used for this screen . OUTPUT: genomic instability and mutation INPUT: AIMS Currently , testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies ( MLH1 , PMS2 , MSH2 and MSH6 ) . If any one of these stains is negative the tumour is considered microsatellite unstable and , if clinical circumstances warrant it , the patient is offered genetic testing for Lynch's syndrome . Due to the binding properties of the mismatch repair heterodimer complexes , gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6 , respectively , but the converse is not true . We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies . METHODS The electronic database of the department of Anatomical Pathology , Royal North Shore Hospital , Sydney , Australia , was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed . An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken . Unusual or discordant cases were reviewed and , in some cases , re-stained to confirm the staining pattern . RESULTS Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry , 104 displayed loss of at least one mismatch repair protein . Of these , 100 showed concordant mismatch repair loss ( i.e. , loss of MLH1 and PMS2 or loss of MSH2 and MSH6 ) . The four discordant cases comprised two single negative cases ( 1 MSH6 negative/MSH2 positive case , 1 PMS2 negative/MLH1 positive ) and two triple negative ( both MLH1/PMS2/MSH6 negative ) . The microsatellite instability ( MSI ) group showed a relatively high median age ( 69.3 years ) due to the departmental policy of testing all cases with possible MSI morphology regardless of age . CONCLUSIONS The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6 , compared to a four panel test , is 100% . No false negatives or positives were identified . We conclude that the two panel test should replace a four panel protocol for immunohistochemical screening for mismatch repair deficiency . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot126

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Breast cancer is the malignant neoplasia with the highest incidence in women worldwide . Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression . Human studies have not considered the complexity of tumor biology during the stages of cancer advance , limiting their clinical application . The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early ( ED ; TNM I and II ) and advanced disease ( AD ; TNM III and IV ) of patients diagnosed with infiltrative ductal carcinoma breast cancer . Oxidative stress parameters were evaluated by plasmatic lipoperoxidation , carbonyl content , thiobarbituric reactive substances ( TBARS ) , nitric oxide levels ( NO ) , total radical antioxidant parameter ( TRAP ) , superoxide dismutase , and catalase activities and GSH levels . Immune evaluation was determined by TNF-α , IL-1β , IL-12 , and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence . Tissue damage analysis included heart ( total CK and CKMB ) , liver ( AST , ALT , GGT ) , and renal ( creatinine , urea , and uric acid ) plasmatic markers . C-reactive protein ( CRP ) and iron metabolism were also evaluated . Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages . ED was characterized by reduction in catalase , 8-isoprostanes , and GSH levels , with enhanced lipid peroxidation and TBARS levels . AD exhibited more pronounced oxidative status , with reduction in catalase activity and TRAP , intense lipid peroxidation and high levels of NO , TBARs , and carbonyl content . ED patients presented a Th2 immune pattern , while AD exhibited Th1 status . CRP levels and ferritin were increased in both stages of disease . Leukocytes burst impairment was observed in both the groups . Plasma iron levels were significantly elevated in AD . The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators . OUTPUT: tumor promoting inflammation INPUT: PURPOSE Overproduction of reactive oxygen species ( ROS ) intermediates above the functional capability of cellular antioxidants may result in instability of important macromolecules and represents the molecular basis of many diseases including inflammation processes , cardiovascular alterations , cancer etc . The purpose of this study was to determine plasma level of superoxide anion , hydrogen-peroxide and malondialdehyde ( MDA ) as markers of oxidative stress and activities of superoxide dismutase ( SOD ) , catalase ( CAT ) and glutathione peroxidase ( GPx ) as antioxidant enzymes in B-chronic lymphocytic leukemia ( B-CLL ) patients . METHODS The study included 29 untreated B-CLL patients in stage A , and 21 in stages B and C , classified according to the Binet system ; 31 healthy volunteers formed the control group . After centrifugation of heparinized peripheral blood , plasma levels of all investigated parameters were determined using spectrophotometric methods . RESULTS Plasma CAT activity was increased in B-CLL patients compared with control subjects ; also , progression of disease was related with significantly higher plasma activity of CAT . Also , B-CLL patients showed significantly higher plasma concentration of MDA compared with controls . No statistically significant differences of superoxide anion and hydrogen peroxide as well as plasma activity of SOD and GPx between the tested groups were noted . CONCLUSION Increase of CAT activity in B-CLL patients indicates that there is stimulation of the antioxidant enzyme system , while the increase of MDA concentration shows increased lipid peroxidation level . According to these results it could be concluded that an imbalance exists between oxidants and antioxidants in the plasma of B-CLL patients . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot127

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines . Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men . In spite of the current therapeutic options for this cancer entity , many patients die due to metastases in distant organs and acquired chemotherapy resistance . Thus , approaches to provide improvements in outcome and quality of life for such patients are urgently needed . Recently , the polyisoprenylated benzophenone 7-epi-nemorosone , originally collected by honeybees from Clusia rosea and Clusia grandiflora ( Clusiaceae ) , has been described to be a potent antitumoral agent . Here , its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques . Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1(+) sub-line . No cross-resistance was detected . FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1 , G1 , and depletion in the S phase populations . A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot . Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events . Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug . ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2 . Additionally , Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2 . Here , we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer . OUTPUT: sustaining proliferative signaling;resisting cell death INPUT: The NOTCH signaling pathway plays important role in the development of multicellular organisms , as it regulates cell proliferation , survival , and differentiation . In adults , it is essential for the T- or B-lymphocyte lineage commitment . NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients . In this study , the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols . In 19 patients ( 22% ) , activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases ( 10% ) demonstrated FBXW7 mutations ( 2 cases had both NOTCH1 and FBXW7 mutations ) . We also analyzed the relationship of the mutation data between the clinical and biological data of the patients . NOTCH1 and FBXW7 , NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype . However , NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot128

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Prostate cancer is responsible for major deaths globally after lung cancer . However , etiology of prostate cancer is still unknown . Individual risk and incidence of prostate cancer may result from the interaction of genetic susceptibility with exposure to environmental factors such as infectious agents , tobacco , occupational exposure , dietary carcinogens , and/or hormonal imbalances leading to injury of the prostate and to the development of chronic inflammation . About 30% of all human cancers are caused by tobacco smoking and inhaled pollutants . Inflammation is now regarded as an important hallmark of cancer . The present study has been aimed to explore the pro-inflammatory levels in prostate carcinoma patients by examining the serum levels of novel cytokine interleukin-18 ( IL-18 ) expression in tobacco exposed population . A total of 578 ( n = 284 biopsy proven prostate cancer patients , n = 294 controls with and without tobacco exposed population ) were recruited . Serum IL-18 ( Interleukin-18 ) level was done by ELISA . The IL-18 levels between cancer patients and controls within same mode tobacco exposure as tobacco smoking ( overall ) showed significant difference ( P &lt ; 0.0001 ) and further we compared within stratified group , it significantly differ ( P &lt ; 0.0001 ) in bidi and cigarette smoking than control non users . Furthermore , IL-18 levels in tobacco chewers ( overall ) with gutkha and khaini chewers showed significant difference ( P &lt ; 0.01 ) than controls non users . Moreover , the IL-18 levels between cancer patients and controls with in of combined mode chewers smokers and alcohol ( CSA ) , smokers with alcohol showed significant difference ( P &lt ; 0.01 ) than controls . The IL-18 levels also differed significantly ( P &lt ; 0.05 ) with smokers and chewers in higher stages of III and IV , and showed non significant with in lower stages . Tobacco exposure enhance the inflammation in prostate carcinoma patients in stratified group as it have been represented as a risk factors in various cancers , but this study provide further its role that seems to influence inflammation especially in prostate carcinoma . OUTPUT: tumor promoting inflammation INPUT: The authors examined nutritional risk factors for prostate cancer among 9,559 participants in the Prostate Cancer Prevention Trial ( United States and Canada , 1994-2003 ) . The presence or absence of cancer was determined by prostate biopsy , which was recommended during the trial because of an elevated prostate-specific antigen level or an abnormal digital rectal examination and was offered to all men at the trial's end . Nutrient intake was assessed using a food frequency questionnaire and a structured supplement-use questionnaire . Cancer was detected in 1,703 men ; 127 cancers were high-grade ( Gleason score 8-10 ) . There were no associations of any nutrient or supplement with prostate cancer risk overall . Risk of high-grade cancer was associated with high intake of polyunsaturated fats ( quartile 4 vs. quartile 1 : odds ratio = 2.41 , 95% confidence interval ( CI ) : 1.33 , 4.38 ) . Dietary calcium was positively associated with low-grade cancer but inversely associated with high-grade cancer ( for quartile 4 vs. quartile 1 , odds ratios were 1.27 ( 95% CI : 1.02 , 1.57 ) and 0.43 ( 95% CI : 0.21 , 0.89 ) , respectively ) . Neither dietary nor supplemental intakes of nutrients often suggested for prostate cancer prevention , including lycopene , long-chain n-3 fatty acids , vitamin D , vitamin E , and selenium , were significantly associated with cancer risk . High intake of n-6 fatty acids , through their effects on inflammation and oxidative stress , may increase prostate cancer risk . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot129

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVES Recently , it was revealed that carnosine inhibits growth of cells isolated from human malignant glioma . In order to understand how this effect is mediated , experiments were performed that addressed a possible influence of carnosine on energy metabolism . METHODS Cells from the glioma line T98G and primary cultured cells from human malignant glioma were cultivated in the presence of carnosine and inhibitors of cellular energy metabolism . As a specific inhibitor for anaerobic glycolysis , oxamate , and as an inhibitor for mitochondrial oxidative phosphorylation , potassium cyanide , were used , and the influence on ATP production was determined using cell-based assays . RESULTS The experiments identified glycolysis as crucial for ATP production in gliomas . In addition , ATP production by mitochondrial activity did not significantly contribute to ATP production and carnosine was identified to be an inhibitor of the vital anaerobic glycolysis . DISCUSSION Carnosine might be considered as a potential drug for the treatment of malignant glioma or other tumors since it inhibits the glycolytic energy metabolism that is crucial for cancer cells and malignant gliomas as shown in the current study . This is especially interesting since the dipeptide is a naturally occurring substance that should be well tolerated . OUTPUT: cellular energetics INPUT: BACKGROUND/AIMS by reducing the number of ATP molecules produced via aerobic glycolysis , the inhibition of lactic dehydrogenase ( LDH ) should hinder the growth of neoplastic cells without damaging the normal cells which do not rely on this metabolic pathway for their energetic needs . Here , we studied the effect of oxamic and tartronic acids , 2 inhibitors of LDH , on aerobic glycolysis and cell replication of HepG2 and PLC/PRF/5 cells , 2 lines from human hepatocellular carcinomas . METHODS aerobic glycolysis was measured by calculating the amounts of lactic acid formed . The effect on replication was assessed by culturing the cells in both standard conditions and glucose-deprived medium , which was used to shut down aerobic glycolysis . RESULTS the oxamic and tartronic acids inhibited aerobic glycolysis , impaired the growth of both cell lines and also induced an increased expression of p53-upregulated modulator of apoptosis , a signal of cell death . A strong impairment of cell replication by oxamic acid was only found when the cells were cultured in the presence of glucose , indicating that it was for the most part owing to inhibition of aerobic glycolysis . CONCLUSIONS inhibition of aerobic glycolysis achieved by blocking LDH could be useful in the treatment of human hepatocellular carcinomas . Without interfering with glucose metabolism in normal cells , it could hinder cell growth by itself and could also enhance the chemotherapeutic index of associated anticancer agents by decreasing the levels of ATP selectively in neoplastic cells . OUTPUT:

cellular energetics

HoC_dynamic_1_shot130

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Chronic inflammation is a critical component in breast cancer progression . Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines ( IL-1 , IL-6 , TNF-α ) , chemotactic cytokines and their receptors ( CXCR4 , CXCL12 , CXCL8 ) and angiogenic factors ( VEGF ) that often overcome the effect of anti-inflammatory molecules ( IL-4 , IL-10 ) thus evading the host's antitumor immunity . Detailed knowledge , therefore , of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer . HIF-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment . HIF-1α is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors . The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells . Functional crosstalk between HIF-1α and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions . In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation , we investigated the role of the two common p53 and HIF-1α co-regulators SRC-1 and SIRT-1 , in the expression of the highly potent metastatic chemokine receptor CXCR4 . Both SRC-1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND Current treatments have a modest impact on survival of pancreatic cancer patients and this study investigates the interaction between sorafenib and gemcitabine and the molecular pharmacodynamics of this combination . METHODS The pancreatic cancer cells were treated with sorafenib and gemcitabine , alone or in combination . The effects of treatments were evaluated on cell proliferation , cell cycle , apoptosis , phosphorylation of Akt , c-Kit , ERK and VEGFR2 , and expression of genes related to drug activity . RESULTS Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation , and assessment of apoptosis demonstrated that drug associations increased the apoptotic index . Sorafenib reduced c-Kit , ERK and VEGFR2 activation and on the other hand , gemcitabine inhibited Akt phosphorylation . Moreover , quantitative PCR showed that sorafenib modulated the expression of genes related to gemcitabine activity , while gemcitabine induced the expression of RKIP . CONCLUSION These data demonstrate that gemcitabine and sorafenib combination displays a synergistic effect in pancreatic cancer cells . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot131

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Alterations of the epidermal growth factor receptor ( EGFR ) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7 . We have previously shown that this mutant receptor , called DeltaEGFR , confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo . To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation , we examined the gene products that control cell cycle progression . We found that levels of the cyclin-dependent kinase ( CDK ) inhibitor , p27 , were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors . Consequently , CDK2-cyclin A activity was also elevated , concomitant with the RB protein hyperphosphorylation . In addition , activated phosphatidylinositol 3-kinase ( PI3-K ) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors . U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB . Treatment of U87MG.DeltaEGFR cells with LY294002 , a PI3-K inhibitor , caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27 . Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo . These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway . This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: Evidence suggests that stem-like cells are responsible for initiation , maintenance and recurrence of solid tumors , including Glioblastoma Multiforme ( GBM ) . GBM is an intractable , highly lethal tumor of the central nervous system . Although epidermal growth factor receptor ( EGFR ) is highly expressed in many GBMs , anti-EGFR therapies have been unsuccessful as treatment . Few studies have examined EGFR activation in GBM stem cells ( GSCs ) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically . We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy . Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478 . Second messenger pathways operative in these processes were elucidated by immunoblotting . EGFR activated AKT and inactivated GSK3beta in EGFR+/PTEN+ GSCs . AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR+/ PTEN+ GSCs generated and the rate of sphere formation . Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis , likely via inhibition of AKT and activation of GSK3beta . Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation , but dependant on B27 growth supplement . Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro . OUTPUT:

enabling replicative immortality;resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot132

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "This research aims to give a new insight to the relationship between host local immune response and the biological behaviour of the tumor by evaluating of intratumoral natural killer ( NK ) cells and tumor necrosis factor-alpha ( TNFalpha ) expressions in oral squamous cell carcinomas . New paraffin sections of the deepest parts of the 46 cases of oral squamous cell carcinomas were immunohistochemically treated by CD57 , selected as NK cell indicator , and TNFalpha monoclonal antibodies . The tumors were graded according to histopathologic grading scores of invasive margins and categorized into 2 groups as "" good "" and "" poor "" prognostic groups . Fifteen cases , from which could be obtained full clinical data , were clinically staged and because of the scarcity of the cases in each group were divided , again , two groups as group 1 : stage I+stage II and group 2 : stage III+stage IV . The expression levels of CD57 and TNFalpha were evaluated according to histopathologic grading groups and clinical staging groups . The results showed that the density of CD57+cells ( NK cells ) was statistically lower in tumors graded as poor prognostic group compared to the cases in good prognostic group . On the contrary , expression level of TNFalpha was statistically higher in poor prognostic group . These findings suggested that increased secretion of TNFalpha in the tumors , which show high invasive potential , may be one of the facilitating factors for tumor invasion and be responsible from suppression of NK cells . Withdrawal of NK cells in the high invasive tumor areas also reminds the necessity of certain shared genetic rearrangements in tumor cells for getting protected from NK cell attacks and moving ahead within the extracellular matrix ." OUTPUT: activating invasion and metastasis INPUT: "The NF-κB is best known for its role in inflammation . Here we show that constitutive NF-κB activity in cancer cells promotes the biosynthesis of redox scavenger glutathione ( GSH ) , which in turn confers resistance to oxidative stress . Inhibition of NF-κB significantly decreases GSH in several lines of human leukemia and prostate cancer cells possessing high or moderate NF-κB activities . Concomitantly , NF-κB inhibition by pharmacological and molecular means sensitizes "" NF-κB positive "" cancer cells to chemically-induced oxidative stress and death . We propose that inhibition of NF-κB can reduce intracellular GSH in "" NF-κB-positive "" cancers thereby improving the efficacy of oxidative stress-based anti-cancer therapy ." OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot133

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Breast cancer is the malignant neoplasia with the highest incidence in women worldwide . Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression . Human studies have not considered the complexity of tumor biology during the stages of cancer advance , limiting their clinical application . The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early ( ED ; TNM I and II ) and advanced disease ( AD ; TNM III and IV ) of patients diagnosed with infiltrative ductal carcinoma breast cancer . Oxidative stress parameters were evaluated by plasmatic lipoperoxidation , carbonyl content , thiobarbituric reactive substances ( TBARS ) , nitric oxide levels ( NO ) , total radical antioxidant parameter ( TRAP ) , superoxide dismutase , and catalase activities and GSH levels . Immune evaluation was determined by TNF-α , IL-1β , IL-12 , and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence . Tissue damage analysis included heart ( total CK and CKMB ) , liver ( AST , ALT , GGT ) , and renal ( creatinine , urea , and uric acid ) plasmatic markers . C-reactive protein ( CRP ) and iron metabolism were also evaluated . Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages . ED was characterized by reduction in catalase , 8-isoprostanes , and GSH levels , with enhanced lipid peroxidation and TBARS levels . AD exhibited more pronounced oxidative status , with reduction in catalase activity and TRAP , intense lipid peroxidation and high levels of NO , TBARs , and carbonyl content . ED patients presented a Th2 immune pattern , while AD exhibited Th1 status . CRP levels and ferritin were increased in both stages of disease . Leukocytes burst impairment was observed in both the groups . Plasma iron levels were significantly elevated in AD . The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators . OUTPUT: tumor promoting inflammation INPUT: BACKGROUND Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis . We postulated that therapeutic concentrations of aspirin and pravastatin , especially in combination , may suppress oxidative stress and inflammation in endothelial cells , and this concept was examined in human coronary artery endothelial cells ( HCAECs ) . METHODS Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein ( ox-LDL , 60 microg/ml for 24 hours ) alone , or pre-treated with aspirin ( 1 , 2 or 5 mmol/L ) , pravastatin ( 1 , 5 or 10 micromol/L ) or their combination ( 1 mmol/L aspirin and 5 micromol/L pravastatin ) , followed by ox-LDL treatment . After respective treatment , superoxide anion production , p38 mitogen activated protein kinase and transcription factor NF-kappaB activation , protein expression of lectin-like ox-LDL receptor-1 ( LOX-1 ) and adhesion molecules , and monocyte adhesion were measured . RESULTS Ox-LDL treatment greatly elicited its receptor LOX-1 expression , superoxide anion production and inflammatory response , which were minimally affected by low concentration of aspirin ( 1 mmol/L ) or pravastatin ( 5 micromol/L ) , but were markedly decreased by their combination . Activation of p38 mitogen activated protein kinase and NF-kappaB , the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-1 , which were only mildly affected by aspirin or pravastatin alone , were significantly attenuated by their combination . As a consequence , monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents . Well-known anti-oxidants alpha-tocopherol and gamma-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin . CONCLUSIONS These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial biology . Anti-oxidant and subsequent anti-inflammatory effect may be one of the potential underling mechanisms . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot134

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Pancreatic ductal adenocarcinoma ( PDAC ) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate . Immunosuppressive cell populations , e.g. regulatory T cells ( Treg ) , appear to be important in PDAC , contributing to patient's poor prognosis . Therefore , we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance . We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg . Remarkably , these cells exhibited the effector/memory phenotype , suggesting their enhanced suppressive activity and higher proliferation capacity . Although we observed a steady increase in transforming growth factor-β ( TGF-β ) levels in the tumors , treatment with a specific inhibitor of TGF-β receptor I kinase failed to abrogate Treg accumulation . A CCR4 antagonist did not affect Treg percentage in the tumor either . However , intense Treg cell division in the tumor microenvironment was demonstrated , suggesting local proliferation as a major mechanism of Treg accumulation in PDAC . Notably , this accumulation was reduced by low-dose gemcitabine administration , resulting in a modestly increased survival of PDAC mice . Our results provide an insight into mechanisms of immunosuppression in PDAC , suggesting an important role for proliferative expansion of effector/memory Treg . Low-dose gemcitabine therapy selectively depletes Treg , providing a basis for new modalities of PDAC therapy . OUTPUT: avoiding immune destruction INPUT: Application of adenovirus vectors ( Adv ) in metastatic cancer treatment is limited . We previously demonstrated that covalent conjugation of polyethleneglycol ( PEG ) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration , but the level of immune response to PEGylated Adv ( PEG-Ad ) was not examined . Here , we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response . We constructed a set of PEG-Ad using 5-kDa PEG , with modification rates of 30% , 45% and 90% . After systemic administration of Advs to rats , we examined the level of anti-Adv immunoglobulin ( Ig)G and IgM in serum . The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group . Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv , whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate , and expressed tumor necrosis factor-alpha , significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv , with negligible side effects . These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer . OUTPUT:

activating invasion and metastasis;tumor promoting inflammation

HoC_dynamic_1_shot135

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Folate ( vitamin B9 ) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate ( dTMP ) and s-adenosylmethionine ( AdoMet ) . The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance , but still unclear . We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis , which is prominent in prostate cells . We , therefore , hypothesized that prostate cells might be highly susceptible to genetic , epigenetic and phenotypic changes consequent to folate restriction . RESULTS We studied the consequences of long-term , mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate ( TRAMP ) model , recapitulating different stages of prostate cancer ; benign , transformed and metastatic . High-performance liquid chromatography analysis demonstrated that mild folate depletion ( 100 nM ) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines . Random oligonucleotide-primed synthesis ( ROPS ) revealed a significant increase in uracil misincorporation and DNA single strand breaks , while spectral karyotype analysis ( SKY ) identified five novel chromosomal rearrangements in cells grown with mild folate depletion . Using global approaches , we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine , indicating a broad effect of folate depletion on epigenetic regulation . These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion . CONCLUSIONS This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological amounts of folate ( 2 microM ) routinely used in tissue culture . In addition , we elucidate for the first time the contribution of these aspects to consequent phenotype changes in epithelial cells . These results provide a strong rationale for studying the effects of folate manipulation on the prostate in vivo , where cells might be more sensitive to changes in folate status resulting from folate supplementation or antifolate therapeutic approaches . OUTPUT: genomic instability and mutation INPUT: BACKGROUND Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia ( BPH ) and prostate carcinoma . The prostate is comprised of a functional secretory epithelium , a basal epithelium , and a supporting stroma comprised of structural elements , and a spectrum of cell types that includes smooth muscle cells , fibroblasts , and inflammatory cells . As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions , discordance within the stroma could permit or promote disease processes . In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology . METHODOLOGY/PRINCIPAL FINDINGS We quantitated transcript levels in microdissected glandular-adjacent stroma from young ( age 4 months ) and old ( age 20-24 months ) C57BL/6 mice , and identified a significant change in the expression of 1259 genes ( p<0.05 ) . These included increases in transcripts encoding proteins associated with inflammation ( e.g. , Ccl8 , Ccl12 ) , genotoxic/oxidative stress ( e.g. , Apod , Serpinb5 ) and other paracrine-acting effects ( e.g. , Cyr61 ) . The expression of several collagen genes ( e.g. , Col1a1 and Col3a1 ) exhibited age-associated declines . By histology , immunofluorescence , and electron microscopy we determined that the collagen matrix is abundant and disorganized , smooth muscle cell orientation is disordered , and inflammatory infiltrates are significantly increased , and are comprised of macrophages , T cells and , to a lesser extent , B cells . CONCLUSION/SIGNIFICANCE These findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot136

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence . Consistent with this role , p21 is a downstream target of several tumour suppressors and oncogenes , and it is downregulated in the majority of tumours , including breast cancer . Here , we report that protein arginine methyltransferase 6 ( PRMT6 ) , a type I PRMT known to act as a transcriptional cofactor , directly represses the p21 promoter . PRMT6 knock-down ( KD ) results in a p21 derepression in breast cancer cells , which is p53-independent , and leads to cell cycle arrest , cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency ( SCID ) mice for all the cancer lines examined . We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence , and it restores their ability to grow on soft agar . We conclude that PRMT6 acts as an oncogene in breast cancer cells , promoting growth and preventing senescence , making it an attractive target for cancer therapy . OUTPUT: enabling replicative immortality;sustaining proliferative signaling INPUT: The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types , but the molecular link between growth factors and c-Jun activation has been enigmatic . In this study we identify a previously uncharacterized RING-domain-containing protein , RACO-1 ( RING domain AP-1 co-activator-1 ) , as a c-Jun co-activator that is regulated by growth factor signalling . RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation , and was both necessary and sufficient for c-Jun/AP-1 activation . Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein . Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1 , which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues . RACO-1 depletion reduced cellular proliferation and decreased expression of several growth-associated AP-1 target genes , such as cdc2 , cyclinD1 and hb-egf . Moreover , transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation . Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot137

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Androgens and the androgen receptor ( AR ) play important roles in the development of male urogenital organs . We previously found that mice with total AR knockout ( ARKO ) and epithelial ARKO failed to develop normal prostate with loss of differentiation . We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate . However , AR roles of stromal fibroblasts in prostate development remain unclear . METHODS To further probe the stromal fibroblast AR roles in prostate development , we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts ( FSP-ARKO ) . We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development . RESULTS The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation , increased apoptosis , and decreased collagen composition . Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors . To further confirm these in vivo findings , we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells , as well as decrease of some stromal growth factors . CONCLUSIONS Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate , but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: INTRODUCTION IκB Kinase ε ( IKKε ) is a member of the IKK family which plays an important role in the activation of nuclear factor-κB ( NF-κB ) . Overexpressed in over 30% of breast cancers , IKKε has been recently identified as a potential breast cancer oncogene . The purpose of this study is to examine the therapeutic potential of IKKε siRNA on human breast cancer cells . METHODS Eight siRNAs targeting different regions of the IKKε mRNA were designed , and the silencing effect was screened by quantitative real time RT-PCR . The biological effects of synthetic siRNAs on human breast cancer cells were investigated by examining the cell proliferation , migration , invasion , focus formation , anchorage-independent growth(via soft agar assay ) , cell cycle arrest , apoptosis ( via annexing binding ) , NF-κB basal level , and NF-κB related gene expressions upon the IKKε silencing . RESULTS Silencing of IKKε in human breast cancer cells resulted in decrease of focus formation potential and clonogenicity as well as in vitro cell migration/invasion capabilities . Moreover , knockdown of IKKε suppressed cell proliferation . Cell cycle assay showed that the anti-proliferation effect of IKKε siRNA was mediated by arresting cells in G(0)/G(1) phase , which was caused by down-regulation of cyclin D(1) . Furthermore , we demonstrated that silencing of IKKε inhibited the NF-κB basal activity as well as the Bcl-2 expression . Significant apoptosis was not observed in breast cancer cells upon the silencing of IKKε . The present study provided the first evidence that silencing IKKε using synthetic siRNA could inhibit the invasiveness properties and proliferation of breast cancer cells . CONCLUSIONS Our results suggested that silencing IKKε using synthetic siRNA may offer a novel therapeutic strategy for breast cancer . OUTPUT:

activating invasion and metastasis;evading growth suppressors;sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot138

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A novel compound 2-arylidene-4,7-dimethyl indan-1-one synthesized was screened for anticancer effect against the human breast adenocarcinoma cell line , MCF-7 . An IC50 value of &gt ; or = 80 microM , nontoxic to the normal breast cell line HBL-100 , showed complete inhibition of the MCF-7 cells . Analysis of mechanisms showed nuclear fragmentation and DNA laddering in gel electrophoresis . GSH and GR levels were found to be reduced after the compound treatment . Cell cycle analysis using fluorescent cytometry revealed G2/M phase arrest , which indicates the compound deserves consideration for further studies against cancer . OUTPUT: resisting cell death;evading growth suppressors;sustaining proliferative signaling INPUT: Designed from a high throughput screened hit compound , novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine ( compound 2 ) , a 2-amino-1-thiazolyl imidazole , inhibited tubulin polymerization , interacted with the colchicine-binding sites of tubulins , and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells . Disruption of the microtubule structure in cancer cells by compound 2 was also observed . Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors . Given orally , compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells . We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot139

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND : Previously , we have observed that highly unsaturated dietary ( n-3 ) fatty acids inhibit cell proliferation in conjunction with stimulation of insulin-like growth factor-binding protein ( IGFBP)-6 secretion in Caco-2 cells , a human colon carcinoma cell line . METHODS : To test the converse hypothesis that inhibition of endogenous IGFBP-6 secretion stimulates Caco-2 cell proliferation , cells were transfected with the antisense IGFBP-6 expression construct or pcDNA3 vector only , and single colonies resistant to G418 sulfate were isolated . RESULTS : Our initial studies indicated that three antisense clones grew faster and produced less IGFBP-6 than two pcDNA3 clones , so antisense IGFBP-6 #5 and pcDNA3 #8 were selected for further detailed analysis . Both the control and antisense clones grew in serum-free medium reaching a plateau density at day eight . However , the antisense clone grew at a rate faster than that of the control and reached a final density that was 31 +/- 3% higher than the control . Northern blot , ligand blot and immunoblot analyses revealed that accumulation of IGFBP-6 mRNA and concentrations of IGFBP-6 peptide produced by the antisense clone were decreased by 80-90% compared to the control . The doubling times of the antisense and control clones were 21.9 +/- 0.4 and 24.8 +/- 0.3 h ( P &lt ; 0.05 ) , respectively . Exogenous IGF-I and IGF-II ( 0.2-200 nmol/L ) stimulated proliferation of both the control and antisense clones in a dose-dependent manner , but the relative potency and efficacy of IGF-II was higher in the antisense clone compared to the control . These results indicate that suppression of IGFBP-6 secretion correlates with an increase in the basal rate of Caco-2 cell growth . CONCLUSIONS : Our findings are consistent with the hypothesis that IGFBP-6 inhibits cell growth by binding to endogenously produced IGF-II , thereby preventing IGF-II from interacting with the IGF-I receptor to stimulate cellular proliferation by an autocrine mechanism . OUTPUT: sustaining proliferative signaling INPUT: OBJECTIVE The goal of this study was to investigate the relationship between plasma levels of insulin-like growth factors-1 ( IGF-1 ) and IGF-binding protein-3 ( IGFBP-3 ) and the risk for cervical intraepithelial neoplasia ( CIN ) and cervical cancer . METHODS Plasma levels of IGF-1 and IGFBP-3 of 44 cervical cancer patients , 82 CIN patients and 40 neoplasm-free patients were investigated . Then the associations of the plasma levels of IGF-1 and IGFBP-3 with cervical neoplasm or its clinicopathologic parameters were analyzed . RESULTS The mean IGF-1 concentrations were significantly different among the control , CIN , and cervical cancer groups ; the levels were higher in the CIN group compared to the controls . According to the quartile category , the plasma IGF-1 level was significantly higher ( p=0.0015 ) in the CIN group than in the controls . The IGFBP-3 level showed no association between the controls and CIN groups ( p=0.842 ) . Although the mean IGF-1/IGFBP-3 molar ratio had borderline significance ( p=0.08 ) among the study population , the quartile comparison showed a significantly higher IGF-1/IGFBP-3 molar ratio in the CIN group compared to the control group ( p=0.041 ) . CONCLUSION Plasma levels of IGF-1 and the IGF-1/IGFBP-3 molar ratio might be useful for the development early detection of cervical lesions and used as an adjuvant diagnostic tool for cervical neoplasia after more larger scale research . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot140

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Insulin-like growth factor ( IGF)-I receptor ( IGF-IR ) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas ( BTC ) . We investigated the immunohistochemical expression of elements of the IGF axis , matrilysin , overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC . We also assessed the effect of IGF-IR blockade on signal transduction , proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor , BMS-536924 , and dominant negative IGF-IR ( IGF-IR/dn ) . The effects of IGF-IR blockade was also studied in nude mouse xenograft models . IGF-I was expressed in 60% and IGF-II in 50% of tumors . High expression was associated with tumor size . IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression . Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression . BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin . BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion . This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion . Moreover , IGF-IR blockade was effective against tumors in mice . IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease . BMS-536924 might have significant therapeutic utility . OUTPUT: resisting cell death INPUT: A growing number of studies have demonstrated an association between serum levels of insulin-like growth factors ( IGFs ) and IGF binding protein-3 ( IGFBP-3 ) and increased risk for various cancers . The aim of this study was to evaluate the relationship between levels of IGF-II or IGFBP-3 in cervical scrapes with cervical cancer and precancerous lesions : low-grade squamous intraepithelial lesion ( LSIL ) and high-grade squamous intraepithelial lesion ( HSIL). 4 groups of cases were examined : LSIL ( n=20 ) , HSIL ( n=28 ) , cervical cancer ( n=45 ) , and controls ( n=51 ) . Control subjects were women with normal , HPV DNA-negative Papanicolau ( Pap ) test . IGF-II and IGFBP-3 levels in cervical scrapes were measured by ELISA . Results show that median protein levels of IGF-II were significantly lower in cervical cancer cases vs. controls ( 446.5 ng/mg vs. 1,168.6 ng/mg , p<0.001 ) . Significantly higher values of IGFBP-3 were found in HSIL vs. controls ( median : 549.5 ng/mg vs. 216 ng/mg ; p=0.018 ) , and were not affected by HR HPV infection , meanwhile no significant differences were observed in IGFBP-3 levels between LSIL or cervical cancer as compared to controls . These data suggests that the progression to cervical cancer is associated with alterations in the IGF system and not affected by HR HPV infection . More studies are needed to understand the possible role of IGFBP-3 in cervical carcinogenesis . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot141

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases . OUTPUT: resisting cell death;avoiding immune destruction INPUT: Mode of action ( MOA ) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment . Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models . An MOA analysis , consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment , was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium ( Cr(VI) ) in drinking water . Based on review of the literature , key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract , absorption of Cr(VI) into the intestinal epithelium , oxidative stress and inflammation , cell proliferation , direct and/or indirect DNA modification , and mutagenesis . Although available data generally support the plausibility of these key events , several unresolved questions and data gaps were identified , highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range . Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species . This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment . OUTPUT:

genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot142

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC₅₀ value of 5 μg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 μg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation . OUTPUT: evading growth suppressors;resisting cell death INPUT: Histone deacetylase inhibitors induce cell cycle arrest and apoptosis in tumor cells and are , therefore , promising anti-cancer drugs . The cyclin-dependent kinase inhibitor p21 is activated in histone deacetylase ( HDAC ) inhibitor-treated tumor cells , and its growth-inhibitory function contributes to the anti-tumorigenic effect of HDAC inhibitors . We show here that induction of p21 by trichostatin A involves MAP kinase signaling . Activation of the MAP kinase signaling pathway by growth factors or stress signals results in histone H3 serine 10 phosphorylation at the p21 promoter and is crucial for acetylation of the neighboring lysine 14 and recruitment of activated RNA polymerase II in response to trichostatin A treatment . In non-induced cells , the protein phosphatase PP2A is associated with the p21 gene and counteracts its activation . Induction of p21 is linked to simultaneous acetylation and phosphorylation of histone H3 . The dual modification mark H3S10phK14ac at the activated p21 promoter is recognized by the phospho-binding protein 14-3-3ζ , which protects the phosphoacetylation mark from being processed by PP2A . Taken together we have revealed a cross-talk of reversible phosphorylation and acetylation signals that controls the activation of p21 by HDAC inhibitors and identify the phosphatase PP2A as chromatin-associated transcriptional repressor in mammalian cells . OUTPUT:

evading growth suppressors;sustaining proliferative signaling

HoC_dynamic_1_shot143

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Liver cancer , predominantly hepatocellular carcinoma ( HCC ) , represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation . Due to dismal prognosis and limited therapeutic intervention , chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC . Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties . We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine ( DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 ( Nrf2)-mediated antioxidant mechanisms . Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB ( NF-κB)-regulated inflammatory pathway , our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion ( PE ) during DENA-induced rat hepatocarcinogenesis . Rats were administered with PE ( 1 or 10 g/kg ) 4 weeks before and 18 weeks following DENA initiation . There was a significant increase in hepatic expressions of inducible nitric oxide synthase , 3-nitrotyrosine , heat shock protein 70 and 90 , cyclooxygenase-2 and NF-κB in DENA-exposed rat livers . PE dose-dependently suppressed all aforementioned elevated inflammatory markers . A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography . Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-κB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis . Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits , namely , Nrf2-mediated redox signaling and NF-κB-regulated inflammatory pathway , by pomegranate phytoconstituents to achieve chemoprevention of HCC . OUTPUT: tumor promoting inflammation INPUT: Accumulating evidence from epidemiological studies indicates that chronic inflammation and oxidative stress play critical roles in neoplastic development . The aim of this study was to investigate the anti-inflammatory , anti-oxidative stress activities , and differential regulation of Nrf2-mediated genes by tea Chrysanthemum zawadskii ( CZ ) and licorice Glycyrrhiza uralensis ( LE ) extracts . The anti-inflammatory and anti-oxidative stress activities of hexane/ethanol extracts of CZ and LE were investigated using in vitro and in vivo approaches , including quantitative real-time PCR ( qPCR ) and microarray . Additionally , the role of the transcriptional factor Nrf2 ( nuclear erythroid-related factor 2 ) signaling pathways was examined . Our results show that CZ and LE extracts exhibited potent anti-inflammatory activities by suppressing the mRNA and protein expression levels of pro-inflammatory biomarkers IL-1β , IL-6 , COX-2 and iNOS in LPS-stimulated murine RAW 264.7 macrophage cells . CZ and LE also significantly suppressed the NO production of LPS-stimulated RAW 264.7 cells . Additionally , CZ and LE suppressed the NF-κB luciferase activity in human HT-29 colon cancer cells . Both extracts also showed strong Nrf2-mediated antioxidant/Phase II detoxifying enzymes induction . CZ and LE induced NQO1 , Nrf2 , and UGT and antioxidant response element ( ARE)-luciferase activity in human hepatoma HepG2 C8 cells . Using Nrf2 knockout [ Nrf2 ( -/-) ] and Nrf2 wild-type ( +/+ ) mice , LE and CZ showed Nrf2-dependent transactivation of Nrf2-mediated antioxidant and phase II detoxifying genes . In summary , CZ and LE possess strong inhibitory effects against NF-κB-mediated inflammatory as well as strong activation of the Nrf2-ARE-anti-oxidative stress signaling pathways , which would contribute to their overall health promoting pharmacological effects against diseases including cancer . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot144

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases . OUTPUT: resisting cell death;avoiding immune destruction INPUT: INTRODUCTION The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood . Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis . METHODS Expression of Tumor necrosis factor-alpha ( TNF-α ) was analyzed in colorectal cancer specimen and the cancer cell line HT-29 by immunohistochemistry and RT-PCR . TNF-α expression on protein and mRNA level were correlated with clinical characteristics and impact on survival . TNFR-1 was co-labelled with TNF-α and CD8+ cytotoxic T cells in immunofluorescence double staining experiments . RESULTS 94% ( n=98/104 ) of the patients with CRC expressed TNF-α . High TNF-α expression was significantly associated with positive lymph node stage and recurrence of the tumor . Multivariate analysis revealed high TNF-α expression as an independent prognostic factor . Immunohistochemistry was correlated with RT-PCR results ( τ=0.794 ) . Immunofluorescence double staining experiments revealed increased TNFR-1 expression by CD8+ cells . CONCLUSIONS TNF-α expression by tumor cells may be an efficient immunological escape mechanism by inflammation-enhanced metastases and probably by induction of apoptosis in tumor-infiltrating CD8+ immune cells resulting in a down regulation of the tumoral immune response . Our data support the role of tumor-derived TNF-α expression as an important promoter of tumoral immune escape mechanisms and malignant progression , and suggest that analysis on either protein ( immunohistochemistry ) or RNA level ( RT-PCR ) can be used effectively in this respect . Targeting TNF-α may be a promising option , especially in cases with high TNF-α expression and positive lymph node metastases . OUTPUT:

tumor promoting inflammation;activating invasion and metastasis

HoC_dynamic_1_shot145

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The role of regulatory T cells ( T(regs) ) in human colon cancer ( CC ) remains controversial : high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study . In mouse models of cancer , T(regs) have been reported to suppress inflammation and protect the host , suppress T cells and protect the tumor , or even have direct cancer-promoting attributes . These different effects may result from the presence of different T(reg) subsets . We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive , but compromised anti-inflammatory , properties ; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt . T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis . Indeed , ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions , suppressed inflammation , improved polyp-specific immune surveillance , and severely attenuated polyposis . Ablation of interleukin-6 ( IL-6 ) , IL-23 , IL-17 , or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt . Surprisingly , loss of IL-17A had a dual effect : IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer . Thus , we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation , potency of immune surveillance , and severity of disease outcome . OUTPUT: tumor promoting inflammation INPUT: Levels of regulatory T cells ( Tregs ) are increased in different cancer types as well as in inflammatory diseases , such as rheumatoid arthritis . Treg accumulation may result from aberrant proliferation and trafficking as well as greater resilience to oxidative stress compared with conventional T cells . This enhanced antioxidative capacity of Tregs possibly serves as feedback inhibition during inflammation and prevents uncontrolled immune reactions by favoring survival of suppressor rather than effector cells . In this study , we demonstrate that human Tregs express and secrete higher levels of thioredoxin-1 , a major antioxidative molecule . Thioredoxin-1 has an essential role in maintaining their surface thiol density as the first line of antioxidative defense mechanisms and is sensitive to proinflammatory stimuli , mainly tumor necrosis factor-α , in a nuclear factor-κB-dependent fashion . The antiapoptotic and oncogenic potential of ( secreted ) Trx-1 suggests that it may exert effects in Tregs beyond redox regulation . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot146

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Colorectal cancer ( CRC ) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor , and thus is an useful model for studying metabolic shift . In the present study , we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry ( GC/MS ) and liquid chromatography tandem mass spectrometry ( LC/MS/MS ) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC . Colonic tissues including tumor , polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study . The metabolic profiles were obtained using GC/MS and LC/MS/MS . Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues . Various amino acids and lipids in the polyps and tumors were elevated , suggesting higher energy needs for increased cellular proliferation . In contrast , significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis . In addition , the accumulation of hypoxanthine and xanthine , and the decrease of uric acid concentration , suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC . Further , there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors . It appears that to gain a growth advantage , cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment . OUTPUT: cellular energetics INPUT: BACKGROUND Apoptosis , a widely important mechanism that contributes to cell growth reduction , is reported to be induced by Crocus sativus in different cancer types . The present study was designed to elucidate apoptosis induction by crocin , a main component of Crocus sativus in a human pancreatic cancer cell line ( BxPC-3 ) . METHODS Cell viability was measured by MTT assay , Hoechest33258 staining was used to detect the chromatin condensation characteristic of apoptosis , and DNA fragmentation was assessed by gel electrophoresis and cell cycle analysis by flow cytometry . RESULTS Crocin induced apoptosis and G1-phase cell cycle arrest of BxPC-3 cells , while decreasing cell viability in a dose dependent and time dependent manner . Cells treated with 10μg/L crocin exhibited apoptotic morphology ( brightly blue-fluorescent condensed nuclei on Hoechst 33258 staining ) and reduction of volume . DNA analysis revealed typical ladders as early as 12 hours after treatment indicative of apoptosis . CONCLUSION Our preclinical study demonstrated a pancreatic cancer cell line to be highly sensitive to crocin-mediated growth inhibition and apoptotic cell death . Although the molecular mechanisms of crocin action are not yet clearly understood , it appears to have potential as a therapeutic agent . OUTPUT:

evading growth suppressors;resisting cell death

HoC_dynamic_1_shot147

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVE To study the clinicopathologic features , immunophenotype and ultrastructural features of sinonasal inflammatory myofibroblastic tumors ( IMT ) . METHODS The clinical and histologic features of 5 cases of sinonasal IMT were reviewed . Immunohistochemical study for vimentin , MSA , SMA , calponin , h-caldesmon , desmin , ALK , fibronectin , CK , S-100 and Ki-67 was carried out . Ultrastructural examination was also performed in two of the cases . RESULTS The patients age ranged from 28 to 62 years ( mean = 43 years ) . The male-to-female ratio was 2:3 . The clinical presentation included nasal obstruction , nasal discharge , nasal bleeding , facial pain , facial swelling , toothache and tear overflow . All of the 5 patients suffered from disease relapses ; and 4 of them had recurrences for more than 5 times . One patient had lymph node metastasis and 3 patients died of the disease . Histologically , the tumor cells were arranged in interlacing fascicles and sometimes haphazard in fashion . They were spindly in shape , cytoplasm eosinophilic with mild nuclear atypia and a low mitotic activity . The intervening stroma was myxoid in appearance accompanied by lymphocyte and plasma cell infiltration , abundant blood vessels and focal collagenized areas . In 3 of the recurrent cases , the tumor cells displayed increased nuclear atypia and mitotic activity ( average about 5 to 6 per 10 high-power fields ) , accompanied by patchy necrosis , less inflammatory cell infiltration and focal sarcomatous changes . Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin . SMA , MSA , calponin and fibronectin were variably expressed . Desmin was weakly positive in 1 case . The staining for h-caldesmon , ALK , S-100 and CK was negative . The Ki-67 proliferation index increased with tumor recurrences . Electron microscopy revealed abundant rough endoplasmic reticulum and dense body formation in the cytoplasm . There were an increased amount of collagen fibers in the stroma . CONCLUSIONS IMT rarely occurs in nasal cavity and paranasal sinuses . The tumor is prone to local invasion and recurrences , with subsequent progression to frank malignancy and distant metastasis , resulting in high mortality and poor prognosis . Complete surgical resection remains the main modality of treatment . OUTPUT: activating invasion and metastasis;resisting cell death;tumor promoting inflammation;sustaining proliferative signaling INPUT: BACKGROUND AND AIMS breast reconstruction with silicone prosthesis following nipple-sparing mastectomy has become widely accepted as a reconstruction option in women requiring mastectomy for cancer . The purpose of this study was to evaluate the incidence and some factors influencing early local complications in patients undergoing NSM with immediate implant reconstruction . MATERIAL AND METHODS prospective study was performed on a consecutive series of 214 breast reconstructions in 205 patients . All complications during the six weeks after surgery were recorded. 42 prostheses were implanted after neoadjuvant chemotherapy , 27 patients previously had radiotherapy due to breast conserving surgery and in all other cases surgery was the pri-mary treatment for cancer . RESULTS the overall six-week complication rate was 16% ( 35 ) and included : major skin flap necrosis ( 4% , 9 procedures ) , minor skin necrosis ( 3% , 7 ) , major infection ( 2% , 5 ) , minor infection ( 3% , 7 ) , prolonged seroma formation ( 3% , 6 ) , haematoma ( 1% , 2 ) and epidermolysis ( 1% , 2 ) . In 6% ( 12 ) reconstruction procedures explantation of prosthesis was done . Neoadjuvant chemo-therapy and radiotherapy were not associated with higher rate of complications . CONCLUSION nipple-sparing mastectomy with immediate implant reconstruction has acceptable morbidity rate in the hand of experienced oncoplastic surgeon and therefore should be considered as treatment option to women requiring mastectomy . OUTPUT:

resisting cell death

HoC_dynamic_1_shot148

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Certain hexavalent chromium ( Cr(VI) ) compounds are well established occupational respiratory tract carcinogens . However , despite extensive studies , the cellular and molecular mechanisms underlying Cr(VI)-induced lung cancer remain poorly understood . In fact , the models used were often suboptimal and yielded conflicting results that were heavily dependent upon the system and experimental conditions employed . Here , we investigated the effects of chronic subcytotoxic and mildly cytotoxic ( 0.1-2 microM ) Cr(VI) exposures on cultures of human bronchial epithelial cells , the main targets of Cr(VI) carcinogenicity . Our studies with the nontumorigenic BEAS-2B cell line suggest that relatively short exposures ( h ) to sublethal Cr(VI) doses ( 0.1-1 microM ) may render these cells less sensitive to contact inhibition . We have also observed a reduced sensitivity to Cr(VI)-induced apoptosis shortly after the beginning of exposure to a mildly cytotoxic Cr(VI) dose ( 2 microM ) . Further studies are needed to determine whether these two phenotypes are involved in the Cr(VI)-induced carcinogenic process . Additionally , evidence gathered in this study strongly points to a Cr(VI) interference with cell adhesion to the substratum and with cell-cell interactions . Finally , by chronically exposing BEAS-2B cells to mildly cytotoxic Cr(VI) doses ( 1 and 2 microM ) , we were able to induce changes in cell morphology and pattern of growth characteristic of an early phase of pre-malignant progression . OUTPUT: evading growth suppressors;resisting cell death INPUT: Quercetin is a flavonoid with anticancer properties . In this study , we examined the effects of quercetin on cell cycle , viability , and proliferation of cancer cells , either singly or in combination with the microtubule-targeting drugs taxol and nocodazole . Although quercetin induced cell death in a dose-dependent manner , 12.5-50 μM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines . Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 h . This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells . However , quercetin did not inhibit the microtubule targeting of taxol or nocodazole . Despite the short-term protection of cells by quercetin , colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination . The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin . We conclude that although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival , the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot149

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Squamous cell carcinoma ( SCC ) is the most frequent cancer in organ transplant recipients ( OTRs ) . The immune system plays a major role in the fight against SCC , however , little is known about the local inflammatory response in SCC at all . We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs . RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis . SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4 , CD8 , TBET , GATA-3 , FOXP3 , RORC , IFN-gamma , IL-4 , TGF-beta , IL-10 , and IL-17A mRNA expression . Immunohistochemistry was carried out in SCC for CD3 , CD4 , CD8 , and FOXP3 expression . Considerable inflammation was seen in both patient groups . SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature . CD4(+) mRNA was diminished in immunosuppression . Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients . T-BET and IFN-gamma mRNA expression were decreased in the OTR group . Although Th17-weighted inflammation was unchanged , IL-17A mRNA level was markedly decreased with immunosuppression . Regulatory T cells , characterized by FOX-P3 and TGF-beta mRNA level , were decreased in OTRs . Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients . OUTPUT: tumor promoting inflammation;avoiding immune destruction INPUT: The incidence of oral squamous cell carcinoma ( SCC ) is increasing but the long-term survival rate remains low . An animal model would therefore be helpful for evaluation of new treatment modalities for oral SCC . Hamster is small animal , therefore , the cancer of hamster cheek pouch is not optimal for tumor imaging . The VX2 cell line has been used in many carcinoma-related studies , including oral SCC research , but it is derived from cutaneous tissue and not mucosa . We chemically induced tongue squamous cell carcinoma in rabbits and subsequently established a rabbit squamous cell line . The cells grew in multiple layers without contact inhibition for 60 passages over 2 years and were positive for cytokeratin ( CK ) . Electron microscopy revealed that cells were polygonal with rich microvilli on the surface , and there were desmosomes between cells and bundles of tonofibril beside the cell membrane . The chromosome number ranged from 71 to 272 , with a modal value of 145 ( 12.4% ) . The cells were transplantable into nude mice subcutaneously or rabbit submucosally and produced carcinomas in all the animals . The cell line should be a useful tool for the study of the biological characteristics of oral SCC , especially tongue SCC . OUTPUT:

evading growth suppressors

HoC_dynamic_1_shot150

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Identification of the proteins that are associated with estrogen receptor ( ER ) status is a first step towards better understanding of the hormone-dependent nature of breast carcinogenesis . Although a number of gene expression analyses have been conducted , protein complement has not been systematically investigated to date . Because proteins are primary targets of therapeutic drugs , in this study , we have attempted to identify proteomic signatures that demarcate ER-positive and -negative breast cancers . Using highly enriched breast tumor cells , replicate analyses from 3 ERα+ and 3 ERα- human breast tumors resulted in the identification of 2,995 unique proteins with ≥2 peptides . Among these , a number of receptor tyrosine kinases and intracellular kinases that are abundantly expressed in ERα+ and ERα- breast cancer tissues were identified . Further , label-free quantitative proteome analysis revealed that 236 proteins were differentially expressed in ERα+ and ERα- breast tumors . Among these , 141 proteins were selectively up-regulated in ERα+ , and 95 proteins were selectively up-regulated in ERα- breast tumors . Comparison of differentially expressed proteins with a breast cancer database revealed 98 among these have been previously reported to be involved in breast cancer . By Gene Ontology molecular function , dehydrogenase , reductase , cytoskeletal proteins , extracellular matrix , hydrolase , and lyase categories were significantly enriched in ERα+ , whereas selected calcium-binding protein , membrane traffic protein , and cytoskeletal protein were enriched in ERα- breast tumors . Biological process and pathway analysis revealed that up-regulated proteins of ERα+ were overrepresented by proteins involved in amino acid metabolism , proteasome , and fatty acid metabolism , while up-regulated proteins of ERα- were overrepresented by proteins involved in glycolysis pathway . The presence and relative abundance of 4 selected differentially abundant proteins ( liprin-α1 , fascin , DAP5 , and β-arrestin-1 ) were quantified and validated by immunohistochemistry . In conclusion , unlike in vitro cell culture models , the in vivo signaling proteins and pathways that we have identified directly from human breast cancer tissues may serve as relevant therapeutic targets for the pharmacological intervention of breast cancer . OUTPUT: cellular energetics INPUT: C-reactive protein is produced in response to cytokines such as interleukin ( IL)-6 . It is known that increased plasma IL-6 levels induce increased hepatic and intratumoral production of C-reactive protein . Cyclooxygenase enzyme-2 is induced by various stimuli , including inflammation and various growth factors . Expression of these two markers has not been well studied in clear cell renal cell carcinoma . The objective of this study is to correlate the expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma with pathologic parameters . A search of the surgical pathology and consultation files at our institution was performed for nephrectomy specimens with clear cell renal cell carcinoma from 2007 to 2008 . Immunohistochemical stains for C-reactive protein and cyclooxygenase enzyme-2 were performed . Staining intensity was graded as 0 , 1+ , 2+ , and 3+ . The staining intensity was then correlated with pathologic stage and Fuhrman nuclear grade for each case . A total of 110 cases were identified . Strong expression of C-reactive protein was associated with higher Fuhrman nuclear grade and pathologic stage , and the strength of correlation was statistically significant ( p = 0.01 and p = 0.001 ) , respectively . However , cyclooxygenase enzyme-2 expression did not show statistically significant correlation with both pathologic stage and Fuhrman nuclear grade ( p = 0.1 and p = 0.15 ) , respectively . To our knowledge , this is the largest study to date correlating the expression of both C-reactive protein and cyclooxygenase enzyme-2 in tissue with pathologic parameters in patients with clear cell renal cell carcinoma , which could have significant prognostic and therapeutic implications . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot151

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Human Barrett's cancer cell lines have numerous , poorly-characterized genetic abnormalities and , consequently , those lines have limited utility as models for studying the early molecular events in carcinogenesis . Cell lines with well-defined genetic lesions that recapitulate various stages of neoplastic progression in Barrett's esophagus would be most useful for such studies . METHODOLOGY/PRINCIPAL FINDINGS To develop such model cell lines , we started with telomerase-immortalized , non-neoplastic Barrett's epithelial ( BAR-T ) cells , which are spontaneously deficient in p16 , and proceeded to knock down p53 using RNAi , to activate Ras by introducing oncogenic H-Ras(G12V) , or both . BAR-T cells infected with either p53 RNAi or oncogenic H-Ras(G12V) alone maintained cell-to-cell contact inhibition and did not exhibit anchorage-independent growth in soft agar . In contrast , the combination of p53 RNAi knockdown with expression of oncogenic H-Ras(G12V) transformed the p16-deficient BAR-T cells , as evidenced by their loss of contact inhibition , by their formation of colonies in soft agar , and by their generation of tumors in immunodeficient mice . CONCLUSIONS/SIGNIFICANCE Through these experiments , we have generated a number of transformed and non-transformed cell lines with well-characterized genetic abnormalities recapitulating various stages of carcinogenesis in Barrett's esophagus . These lines should be useful models for the study of carcinogenesis in Barrett's esophagus , and for testing the efficacy of chemopreventive and chemotherapeutic agents . OUTPUT: evading growth suppressors INPUT: BACKGROUND To identify potential tumor suppressor genes , genome-wide data from exome and transcriptome sequencing were combined to search for genes with loss of heterozygosity and allele-specific expression . The analysis was conducted on the breast cancer cell line HCC1954 , and a lymphoblast cell line from the same individual , HCC1954BL . RESULTS By comparing exome sequences from the two cell lines , we identified loss of heterozygosity events at 403 genes in HCC1954 and at one gene in HCC1954BL . The combination of exome and transcriptome sequence data also revealed 86 and 50 genes with allele specific expression events in HCC1954 and HCC1954BL , which comprise 5.4% and 2.6% of genes surveyed , respectively . Many of these genes identified by loss of heterozygosity and allele-specific expression are known or putative tumor suppressor genes , such as BRCA1 , MSH3 and SETX , which participate in DNA repair pathways . CONCLUSIONS Our results demonstrate that the combined application of high throughput sequencing to exome and allele-specific transcriptome analysis can reveal genes with known tumor suppressor characteristics , and a shortlist of novel candidates for the study of tumor suppressor activities . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot152

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Epidemiological studies exploring the connection between hypertension and cancer incidence find a higher cancer mortality in hypertensive patients , particularly elevated in hypertension associated with a stimulation of the renin-angiotensin-aldosterone system . Primary aldosteronism , with plasma aldosterone levels between 0.5 and 1 nM ( 18-36 ng/dL ) and local aldosterone levels up to 500 nM ( 18,000 ng/dL ) , is now recognised as a more common cause for hypertension . We recently found angiotensin II to be genotoxic due to its induction of oxidative stress . Since aldosterone in higher concentrations also has oxidative effects , its potential genotoxic action in pig LLC-PK1 cells with properties of proximal tubules was analysed . DNA damage was evaluated by two test systems : the comet assay , and the micronucleus frequency test . The results showed that aldosterone concentrations starting from 10 nM ( 360 ng/dL ) caused a significant increase of DNA damage monitored with the comet assay in LLC-PK1 , while there was no change in cell vitality and proliferation . The micronucleus frequency test revealed that 10 nM aldosterone also leads to the formation of micronuclei . Furthermore , the formation of superoxide radicals in the cells by this aldosterone concentration could be detected with the superoxide-specific stain dihydroethidium . Further evidence for oxidative stress-induced DNA damage was its reversibility by the antioxidants tempol and catalase . Addition of the steroidal mineralocorticoid receptor antagonist spironolactone or the novel selective nonsteroidal antagonist ( R)-BR-4628 reduced the DNA damage and the amount of superoxide radicals indicating a receptor-dependent process . OUTPUT: genomic instability and mutation INPUT: The radioprotective effects of dimethyl sulfoxide ( DMSO ) have been known for many years , and the suppression of hydroxyl ( OH ) radicals induced by ionizing radiation has been thought to be the main cause of this effect . However , the DMSO concentration used was very high , and might be toxic , in earlier studies . In the present study , we administered a lower , non-toxic concentration ( 0.5% , i.e. , 64 mM ) of DMSO before irradiation and examined its radioprotective effects . Colony formation assay and micronucleus assay showed significant radioprotective effects in CHO , but not in xrs5 , which is defective in the repair function of DNA double-strand breaks . The levels of phosphorylated H2AX and the formation of 53BP1 foci 15 minutes after irradiation , which might reflect initial DNA double-strand breaks , in DMSO-treated CHO cells were similar to those in non-treated cells , suggesting that the radioprotective effects were not attributable to the suppression of general indirect action in the lower concentration of DMSO . On the other hand , 2 hours after irradiation , the average number of 53BP1 foci , which might reflect residual DNA double-strand breaks , was significantly decreased in DMSO-treated CHO cells compared to non-treated cells . The results indicated that low concentration of DMSO exerts radioprotective effects through the facilitation of DNA double-strand break repair rather than through the suppression of indirect action . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot153

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: A prominent feature of inflammatory diseases is endothelial dysfunction . Factors associated with endothelial dysfunction include proinflammatory cytokines , adhesion molecules , and matrix degrading enzymes . At the transcriptional level , they are regulated by the histone deacetylase sirtuin ( SIRT ) 1 via its actions on the proinflammatory transcription factor nuclear factor-κB ( NF-κB ) . The role of SIRT6 , also a histone deacetylase , in regulating inflammation in endothelial cells is not known . The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells ( HUVECs ) in the presence of lipopolysaccharide ( LPS ) . LPS decreased expression of SIRT6 in HUVECs . Knockdown of SIRT6 increased the expression of proinflammatory cytokines ( IL-1β , IL-6 , IL-8 ) , COX-prostaglandin system , ECM remodelling enzymes ( MMP-2 , MMP-9 and PAI-1 ) , the adhesion molecule ICAM-1 , and proangiogenic growth factors VEGF and FGF-2 ; cell migration ; cell adhesion to leukocytes . Loss of SIRT6 increased the expression of NF-κB , whereas overexpression of SIRT6 was associated with decreased NF-κB transcriptional activity . Taken together , these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation , vascular remodelling , and angiogenesis . SIRT6 may be a potential pharmacological target for inflammatory vascular diseases . OUTPUT: activating invasion and metastasis;inducing angiogenesis;tumor promoting inflammation INPUT: BACKGROUND IL-6 is a pro-inflammatory cytokine that signals via binding to a soluble or membrane bound receptor , while nitric oxide ( NO ) , an oxidative stress molecule , diffuses through the cell membrane without a receptor . Both mediators signal through different mechanisms , yet they are dependent on NFκB . We proposed that both mediators are co-induced and co-regulated in inflamed mammary epithelial cells . METHODS SCp2 mammary epithelial cells were treated with bacterial endotoxin ( ET ) for different time periods and analyzed for induction of IL-6 secretion and NO production by ELISA and Griess reaction , respectively . The expression of IL-6 and induced NO synthase ( iNOS ) was assayed by real time PCR and/or western immunoblots , and the activation of NFκB was assayed by immunobinding assay . To investigate the role of mammary cell microenvironment ( cell-substratum or interaction of mammary epithelial cell types ; critical to mammary development , function , and disease ) in modulation of the inflammatory response , SCp2 cells were cultured with or without extracellular matrix ( EHS ) or in coculture with their myoepithelial counterpart ( SCg6 ) , and assayed for ET-induced IL-6 and NO . RESULTS Endotoxin induced NFκB activation at 1 h after ET application . IL-6 secretion and NO production were induced , but with unexpected delay in expression of mRNA for iNOS compared to IL-6 . NFκB/p65 activation was transient but NFκB/p50 activation persisted longer . Selective inhibition of NFκB activation by Wedelolactone reduced ET-induced expression of IL-6 mRNA and protein but not iNOS mRNA or NO production , suggesting differences in IL-6 and iNOS regulation via NFκB . SCp2 cells in coculture with SCg6 but not in presence of EHS dramatically induced IL-6 secretion even in the absence of ET . ET-induced NO production was blunted in SCp2/SCg6 cocultures compared to that in SCp2 alone . CONCLUSIONS The differential regulation of IL-6 and iNOS together with the differential activation of different NFκB dimers suggest that IL-6 and iNOS are regulated by different NFκB dimers , and differentially regulated by the microenvironment of epithelial cells . The understanding of innate immune responses and inflammation in epithelia and linkage thereof is crucial for understanding the link between chronic inflammation and cancer in epithelial tissues such as the mammary gland . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot154

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer . In this context , heparan sulfate proteoglycans ( HSPGs ) emerge as interesting targets , owing to their function as co-receptors of major , pro-angiogenic factors . Accordingly , previous studies have suggested anti-tumor effects of heparin , i.e. over-sulfated HS , and various heparin mimetics ; however , a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties . Here , we have explored the use of human ScFv anti-HS antibodies ( αHS ) as a more rational approach to target HSPG function in endothelial cells ( ECs). αHS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors , i.e. highly angiogenic brain tumors . Unexpectedly , we found that these αHS exhibited potent pro-angiogenic effects in primary human ECs. αHS were shown to stimulate EC differentiation , which was associated with increased EC tube formation and proliferation . Moreover , αHS supported EC survival under hypoxia and starvation , i.e. conditions typical of the tumor microenvironment . Importantly , αHS-mediated proliferation was efficiently counter-acted by heparin and was absent in HSPG-deficient mutant cells , confirming HS-specific effects . On a mechanistic level , binding of αHS to HSPGs of ECs as well as glioblastoma cells was found to trigger p38 MAPK-dependent signaling resulting in increased proliferation . We conclude that several αHS that recognize HS epitopes abundant in the tumor vasculature may elicit a pro-angiogenic response , which has implications for the development of antibody-based targeting of HSPGs in cancer . OUTPUT: sustaining proliferative signaling;inducing angiogenesis INPUT: Heat shock protein 90 ( Hsp90 ) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation . Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth , leading to the acceptance of Hsp90 as a potential therapeutic target for cancer . Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system , we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity . EC144 , a synthetic Hsp90 inhibitor , blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2 , MEK1/2 , JNK , and p38 MAPK but not NF-κB . Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2 , MEK1/2 , and ERK1/2 . Consequently , EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-α release . Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs . In vivo , semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response . In a mouse collagen-induced arthritis model , EC144 also suppressed disease development , which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells . Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response . OUTPUT:

sustaining proliferative signaling;tumor promoting inflammation

HoC_dynamic_1_shot155

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Lung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils . More detailed information on inflammatory pathways and the role of neutrophils herein is a prerequisite for understanding the mechanism of inflammation associated cancer . METHODS In the present study , we used microarrays in order to obtain a global view of the transcriptional responses of the lung to LPS in mice , which mimics an acute lung inflammation . To investigate the influence of neutrophils in this process , we depleted mice from circulating neutrophils by treatment with anti-PMN antibodies prior to LPS exposure . RESULTS A total of 514 genes was greater than 1.5-fold differentially expressed in the LPS induced lung inflammation model. 394 of the 514 were up regulated genes mostly involved in cell cycle and immune/inflammation related processes , such as cytokine/chemokine activity and signalling . Down regulated genes represented nonimmune processes , such as development , metabolism and transport . Notably , the number of genes and pathways that were differentially expressed , was reduced when animals were depleted from circulating neutrophils , confirming the central role of neutrophils in the inflammatory response . Furthermore , there was a significant correlation between the differentially expressed gene list and the promutagenic DNA lesion M1dG , suggesting that it is the extent of the immune response which drives genetic instability in the inflamed lung . Several genes that were specifically regulated by the presence of activated neutrophils could be identified and these were mostly involved in interferon signalling , oxidative stress response and cell cycle progression . The latter possibly refers to a higher rate of cell turnover in the inflamed lung with neutrophils , suggesting that the neutrophil influx is associated with a higher risk for the accumulation and fixation of mutations . CONCLUSION Gene expression profiling identified specific genes and pathways that are related to neutrophilic inflammation and could be associated to cancer development and indicate an active role of neutrophils in mediating the LPS induced inflammatory response in the mouse lung . OUTPUT: tumor promoting inflammation;genomic instability and mutation INPUT: BACKGROUND Chronic lymphocytic leukemia cells show prolonged survival in vivo , but rapidly die by spontaneous apoptosis in vitro , unless they are co-cultured with stromal cells or non-malignant leukocytes . The objective of this study was to characterize the survival-inducing cross-talk of chronic lymphocytic leukemia cells with their microenvironment to identify novel therapeutic targets . DESIGN AND METHODS We analyzed and compared microarray-based expression profiles of chronic lymphocytic leukemia cells before and after three different survival-inducing culture conditions : ( i ) stromal cell co-culture , ( ii ) stromal cell conditioned medium and ( iii ) high cell density cultures of unsorted peripheral blood mononuclear cells . Cytokine antibody arrays were applied to study the composition of soluble factors present in these cultures . RESULTS The different survival-supportive culture conditions induced distinct gene expression changes , the majority of which were common to all three conditions . Pathway analyses identified - in addition to known signaling networks in chronic lymphocytic leukemia - novel pathways , of which Toll-like receptor signaling , nuclear respiratory factor-2 ( NRF2)-mediated oxidative stress response , and signaling via triggering receptor expressed on myeloid cells-1 ( TREM1 ) were the most relevant . A high proportion of up-regulated genes were inflammatory cytokines , of which chemokine ( C-C motif ) ligand 2 ( CCL2 ) was shown to be induced in monocytes by the presence of chronic lymphocytic leukemia cells in vitro . In addition , increased serum levels of this chemokine were detected in patients with chronic lymphocytic leukemia . CONCLUSIONS Our data provide several lines of evidence that an inflammatory microenvironment is induced in survival-supportive cultures of chronic lymphocytic leukemia cells which might be directly or indirectly involved in the prolonged survival of the malignant cells . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot156

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: INTRODUCTION The insulin-like growth factor I receptor ( IGF-IR ) pathway plays a major role in cancer growth , tumor cell survival and resistance to therapy . BACKGROUND Preclinical evidence that targeting the IGF-IR is effective in cancer treatment has been accumulating for almost 2 decades . Early clinical trials revealed an acceptable safety profile together with pharmacodynamic evidence that the receptor can be targeted successfully . It is premature to draw conclusions regarding the therapeutic potential of this class of compounds but well-documented single-agent activity was noted during phase I evaluations , and recent evidence from a phase-II study suggests that co-administration of an anti-IGF-1R antibody with chemotherapy for non-small-cell lung cancer ( NSCLC ) improves objective response rate and progression-free survival . VIEWPOINTS These early results are a strong indication for continued research on the targeting of IGF-R , particularly in the treatment of NSCLC . CONCLUSIONS Today , IGF-1R targeting appears a promising approach , more than two dozen compounds have been developed and clinical trials are underway . OUTPUT: sustaining proliferative signaling INPUT: Deregulation of insulin-like growth factor-1 receptor ( IGF-1R ) is closely associated with malignant transformation and tumor cell survival in various cancers . We found that IGF-1R expression level in leukemia cells positively correlated with the percentage of blast in bone marrow from de novo acute myeloid leukemia ( AML ) patients . Moreover , we showed that NVP-ADW742 , a novel small weight molecular inhibitor of IGF-IR , could induce apoptosis in both HL-60 cell line and primary AML blasts . However , no significant alteration of cell cycle was observed in HL-60 cells . Further studies revealed that NVP-ADW742 induced Akt dephosphorylation , which might subsequently induce p38 phosphorylation and decrease antiapoptotic protein Bcl-2 expression in HL-60 cells . Finally , we demonstrated that NVP-ADW742 could synergize with Ara-C to induce the kill in a subset of drug-resistant AML specimens . We suggested that IGF-lR targeting might be therapeutically beneficial for some AML patients . OUTPUT:

sustaining proliferative signaling;resisting cell death;evading growth suppressors

HoC_dynamic_1_shot157

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "The induction of apoptosis by glucocorticoids in isolated thymocytes has been studied extensively . However , it is not known whether or not the same changes occur after in vivo glucocorticoid treatment . In order to investigate this , we have studied the changes occurring in thymocytes isolated from rats , from 2-24 hr after a dose of dexamethasone ( 1 mg/kg ) , which caused 50% thymic atrophy . Thymocytes were separated into four fractions by isopycnic Percoll gradients . A loss of cells occurred within 2-8 hr , primarily in only one of the two major fractions of normal thymocytes . This loss of normal thymocytes coincided with the appearance of small dense cells with characteristic features of apoptosis including condensed chromatin , increased DNA fragmentation , internucleosomal DNA cleavage and a "" hypodiploid "" peak on flow cytometric analysis . Striking differences occurred in the cellular composition of the different Percoll fractions with time . Initially ( up to 4 hr ) , the pattern of changes occurring in vivo resembled those found in vitro . However , at later times , the complex fate of apoptotic cells in vivo , such as phagocytosis , are not observed in the in vitro studies ." OUTPUT: resisting cell death INPUT: "Recently , we identified the "" apoptotic ring, "" containing phosphorylated histone H2AX ( γ-H2AX ) , as an early chromatin modification during apoptosis . Because γ-H2AX initiates the DNA damage response ( DDR ) , we tested whether the apoptotic H2AX response leads to the full recruitment of the DDR factors that normally coordinate DNA repair and cell-cycle checkpoints . We show that the apoptotic H2AX response does not recruit the DDR factors because MDC1 ( mediator of DNA damage checkpoint protein 1 ) , which normally binds to γ-H2AX in response to DNA damage and amplifies the DDR , is cleaved by caspase-3 . This cleavage separates the BRCT and FHA domains of MDC1 and constitutes a novel mechanism for the inactivation of DNA repair in apoptotic cells . Also , we show that downregulation of MDC1 increases the apoptotic response to TRAIL . Together , these results implicate MDC1 in the cellular apoptotic response ." OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot158

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Radiation-induced carcinogenesis is a major concern both for astronauts on long-term space missions and for cancer patients being treated with therapeutic radiation . Exposure to radiation induces oxidative stress and chronic inflammation , which are critical initiators and promoters of carcinogenesis . Many studies have demonstrated that non-steroidal anti-inflammatory drugs and antioxidants can reduce the risk of radiation-induced cancer . In this study , we found that a synthetic triterpenoid , CDDO-Me ( bardoxolone methyl ) , was able to protect human colon epithelial cells ( HCECs ) against radiation-induced transformation . HCECs that were immortalized by ectopic expression of hTERT and cdk4 and exhibit trisomy for chromosome 7 ( a non-random chromosome change that occurs in 37% of premalignant colon adenomas ) can be transformed experimentally with one combined exposure to 2 Gy of protons at 1 GeV/nucleon followed 24 h later by 50 cGy of ( 56)Fe ions at 1 GeV/nucleon . Transformed cells showed an increase in proliferation rate and in both anchorage-dependent and independent colony formation ability . A spectrum of chromosome aberrations was observed in transformed cells , with 40% showing loss of 17p ( e.g. loss of one copy of p53 ) . Pretreatment of cells with pharmacological doses of CDDO-Me , which has been shown to induce antioxidative as well as anti-inflammatory responses , prevented the heavy-ion-induced increase in proliferation rate and anchorage-dependent and independent colony formation efficiencies . Taken together , these results demonstrate that experimentally immortalized human colon epithelial cells with a non-random chromosome 7 trisomy are valuable premalignant cellular reagents that can be used to study radiation-induced colorectal carcinogenesis . The utility of premalignant HCECs to test novel compounds such as CDDO-Me that can be used to protect against radiation-induced neoplastic transformation is also demonstrated . OUTPUT: genomic instability and mutation;tumor promoting inflammation INPUT: Carbon nanotubes have a wide range of applications in various industries and their use is likely to rise in the future . Currently , a major concern is that with the increasing use and production of these materials , there may be increased health risks to exposed workers . Long ( &gt ; 15 microm ) straight nanotubes may undergo frustrated phagocytosis which is likely to result in reduced clearance . We examine here the effects of multiwalled carbon nanotubes of different sizes on monocytic THP-1 cells , with regard to their ability to stimulate increased expression of the HO-1 and GST genes and their ability to produce nuclear translocation of the transcription factor , Nrf2 , as well as the release of several pro-inflammatory cytokines and mediators of inflammation . Our results suggest that long ( 50 microm ) carbon nanotubes ( 62.5 microg/ml for 4 hours ) produce increased nuclear translocation of Nrf2 and increased HO-1 gene expression compared with shorter entangled nanotubes . There was no increased gene expression for GST . The long nanotubes ( NT1 ) caused increased release of the proinflammatory cytokine IL-1beta , an effect which was diminished by the antioxidant trolox , suggesting a role of oxidative stress in the upregulation of this cytokine . Tentatively , our study suggests that long carbon nanotubes may exert their effect in THP-1 cells in part via an oxidative stress mechanism . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot159

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Thyroid hormone ( T(3) ) mediates cellular growth , development , and differentiation by binding to the nuclear thyroid hormone receptor ( TR ) . Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma ( HCC ) independent from other major HCC risk factors . Dickkopf ( DKK ) 4 , a secreted protein , antagonizes the Wnt signal pathway . In this study , we demonstrate that T(3) may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA ( mRNA ) and protein levels . DKK4 was down-regulated in 67.5% of HCC cancerous tissues . The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues . Further , TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis . In function assays , stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro . Conversely , knocking down DKK4 restores cell invasiveness . DKK4-expressing J7 clones showed increased degradation of β-catenin , but down-regulation of CD44 , cyclin D1 , and c-Jun . To investigate the effect of DKK4 and TR on tumor growth in vivo , we established a xenograft of J7 cells in nude mice . J7-DKK4 and J7-TRα1 overexpressing mice , which displayed growth arrest , lower lung colony formation index , and smaller tumor size than in control mice , supporting an inhibitory role of DKK4 in tumor progression . CONCLUSION : Taken together , these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR . OUTPUT: activating invasion and metastasis INPUT: RKIP-1 is a metastasis suppressor that is frequently downregulated in aggressive cancers . However , the consequences of RKIP loss in primary or immortalized cells have not yet been explored . Using HEK-293 RKIP depleted ( termed HEK-499 ) and Flp-In T-Rex-293 RKIP inducible cell lines combined with whole transcriptome analysis , we show that RKIP-1 silencing accelerates DNA synthesis and G1/S transition entry by inducing the expression of cdc6 , MCM 2 , 4 , 6 , 7 , cdc45L , cyclin D2 , cyclin E2 , cyclin D1 , SKP2 and the downregulation of p21(cip1) . Moreover , RKIP depletion accelerates the time from nuclear envelop breakdown ( NEB ) to anaphase markedly , while the upregulation of RKIP shortened the NEB to anaphase time . We show that RKIP depletion induces the expression of NEK6 , a molecule known to enhance G2/M transition , and down-regulates G2/M checkpoint molecules like Aurora B , cyclin G1 and sertuin that slow the G2/M transition time . These subtle changes in the kinetics of the cell cycle culminate in a higher proliferation rate of HEK-499 compared to control cells . Finally , we show that RKIP depletion enhances cellular motility by inducing the expression/stabilization of β-catenin , vimentin , MET and PAK1 . Overall , our data suggest that modulation of the cell cycle checkpoints and motility by RKIP may be fundamental to its metastasis suppressive function in cancer and that RKIP role in a cell is more intricate and diverse than previously thought . OUTPUT:

sustaining proliferative signaling;activating invasion and metastasis

HoC_dynamic_1_shot160

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Background . An important goal of personalized cancer therapy is to tailor specific therapies to the mutational profile of individual patients . However , whole genome sequencing studies have shown that the mutational profiles of cancers evolve over time and often differ between primary and metastatic sites . Activating point mutations in the PIK3CA gene are common in primary breast cancer tumors , but their presence in breast cancer bone metastases has not been assessed previously . Results . Fourteen patients with breast cancer bone metastases were biopsied by three methods : CT-guided bone biopsies ; bone marrow trephine biopsies ; and bone marrow aspiration . Samples that were positive for cancer cells were obtained from six patients . Three of these patients had detectable PIK3CA mutations in bone marrow cancer cells . Primary tumor samples were available for four of the six patients assessed for PIK3CA status in their bone metastases . For each of these , the PIK3CA mutation status was the same in the primary and metastatic sites . Conclusions . PIK3CA mutations occur frequently in breast cancer bone metastases . The PIK3CA mutation status in bone metastases samples appears to reflect the PIK3CA mutation status in the primary tumour . Breast cancer patients with bone metastases may be candidates for treatment with selective PIK3CA inhibitors . OUTPUT: genomic instability and mutation;activating invasion and metastasis INPUT: Bone is the second most common metastatic site in patients with renal cell carcinoma presenting with metastases ( mRCC ) at diagnosis . Complications of metastatic bone disease , including bone pain , fractures , spinal cord compression , and hypercalcaemia , are the primary cause of decline in the quality of life of patients with mRCC . Currently , treatment for mRCC bone metastases is generally palliative . Bisphosphonates are also used ; however , the efficacy of bisphosphonates in conjunction with targeted agents is currently unknown . As growth factors play a critical role in the development of bone metastases , there is a biological rationale for the use of targeted agents to treat them . We report here the case of two patients with mRCC with surgically unresectable sacral bone metastases treated with sunitinib , who are still alive with long-term stabilization of metastases of 48 and 31 months . Results suggest targeted agents such as sunitinib may be an effective treatment for bone metastases . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot161

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Anti-angiogenic treatment of glioblastoma characteristically results in therapy resistance and tumor progression via diffuse infiltration . Monitoring tumor progression in these patients is thwarted because therapy results in tumor invisibility in contrast-enhanced ( CE ) MRI . To address this problem , we examined whether tumor progression could be monitored by metabolic mapping using ( 1)H MR spectroscopic imaging ( MRSI ) . METHODS We treated groups of BALB/c nu/nu mice carrying different orthotopic diffuse-infiltrative glioblastoma xenografts with bevacizumab ( anti-vascular endothelial growth factor [ VEGF ] antibody , n = 13 ) , cabozantinib ( combined VEGF receptor 2/c-Met tyrosine kinase inhibitor , n = 11 ) , or placebo ( n = 15 ) and compared CE-MRI with MRS-derived metabolic maps before , during , and after treatment . Metabolic maps and CE-MRIs were subsequently correlated to histology and immunohistochemistry . RESULTS In vivo imaging of choline/n-acetyl aspartate ratios via multivoxel MRS is better able to evaluate response to therapy than CE-MRI . Lactate imaging revealed that diffuse infiltrative areas in glioblastoma xenografts did not present with excessive glycolysis . In contrast , glycolysis was observed in hypoxic areas in angiogenesis-dependent compact regions of glioma only , especially after anti-angiogenic treatment . CONCLUSION Our data present MRSI as a powerful and feasible approach that is superior to CE-MRI and may provide handles for optimizing treatment of glioma . Furthermore , we show that glycolysis is more prominent in hypoxic areas than in areas of diffuse infiltrative growth . The Warburg hypothesis of persisting glycolysis in tumors under normoxic conditions may thus not be valid for diffuse glioma . OUTPUT: cellular energetics;inducing angiogenesis INPUT: Despite the deployment of multimodal therapies involving neurosurgical resection , radio- and polychemotherapy , the prognosis for glioblastoma patients remains poor . These tumors are pathologically characterized by their associated angiogenesis and diffuse brain invasion , processes that are probably closely linked to the unfavorable prognosis of this disease . Accordingly , pharmacological inhibition of glioblastoma invasion and approaches that impede angiogenesis are considered to be promising therapeutic strategies to combat these tumors . Nevertheless , the anti-angiogenic therapies for glioblastoma currently available are transient and palliative at best . Blocking the effects of fibroblast growth factor ( FGF ) may represent a novel mean of inhibiting the angiogenesis associated with glioblastoma , as it mediates the angiogenesis induced by other factors and it is an angiogenic factor by itself . In addition , the survival of glioma cells and their resistance to chemotherapeutic agents are highly FGF-dependent . We show here that a recently described inhibitor of FGF , 2,5-dihydroxyphenyl-sulfonate ( 2,5DHPS , dobesilate ) , stimulates the apoptosis of tumor cells , inhibits glioblastoma invasion and suppresses its associated angiogenesis . Moreover , this agent augments the efficiency of chemotherapeutic agents in a rat model of orthotopic brain tumor . These results suggest that 2,5DHPS treatment may represent a promising therapy for malignant glioma . OUTPUT:

inducing angiogenesis;sustaining proliferative signaling

HoC_dynamic_1_shot162

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Ovarian surface epithelial cells undergo several rounds of division to repair the wound created by follicular rupture at the time of ovulation . This cyclical requirement for cell division , when not interrupted by the long anovulatory rest periods that occur during pregnancy and lactation , may contribute to the development of ovarian cancer . PURPOSE AND METHODS To test this hypothesis , we isolated rat ovarian surface epithelial cells from 10 adult female Fisher rats , initiated two mixed-population and seven clonal cell lines , and repeatedly subcultured these cells in vitro for more than 20 passages . We then tested them for the acquisition of the following four features associated with transformation : 1 ) the loss of contact inhibition , 2 ) the capacity for substrate-independent growth , 3 ) the ability to form tumors when injected subcutaneously and/or intraperitoneally into athymic mice , and 4 ) cytogenetic abnormalities . RESULTS Loss of contact inhibition was observed in all nine late-passage cell lines . Six of the nine late-passage , but none of the early-passage , cell lines tested exhibited a capacity for substrate-independent growth that was augmented in a dose-dependent manner by epidermal growth factor . Two late-passage cell lines ( clone 2 and mixed-population 2 ) generated tumors in athymic BALB/c mice within 3 weeks following subcutaneous injection of 5 x 10(6) cells , whereas similar numbers of early-passage cells from the same cell lines failed to generate palpable tumors . Late-passage clone 7 cells were tumorigenic when 5 x 10(7) cells were injected intraperitoneally . Two of the cell lines analyzed exhibited alterations involving losses of part or all of one member of the chromosome 5 pair . Clone 2 possessed an interstitial deletion , del(5)(q21.3q24) , consistent with the loss of an uncloned putative tumor suppressor gene at 5q22q23 previously reported to reside near the loci for the interferon alpha , interferon beta , and c-jun genes . Early-passage clone 7 cells exhibited chromosome 5 monosomy , while late-passage cells contained one normal chromosome 5 and a derivative ( 5q12q ) . Southern analysis of the three cell lines revealed no consistent loss of loci for the interferon and c-jun genes , although early-passage clone 7 cells had one half the gene copy number for the interferon beta and c-jun genes and both early- and late-passage clone 7 cells lacked DNA sequences hybridizing with the probe for interferon alpha . CONCLUSION This pattern of passage-dependent spontaneous transformation of rat ovarian surface epithelial cells in vitro supports the hypothesis that repetitious ovulation contributes to the etiology of human ovarian cancer . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: Modeling the behavior of mammalian arachnoid cells is critical to understand hydrocephalus and other brain disorders involving abnormal flow of cerebrospinal fluid , yet relatively little is known about the physiology of arachnoid cells due to lack of a robust three-dimensional model system . Explanted primary cultures have been the only option to study transport across arachnoid cell membranes , but practical limitations of primary culture include slow growth , early senescence , and poor reproducibility . The purpose of this study was to create immortalized rat arachnoid cell lines to permit in vitro study of arachnoid granulations and properties of cerebrospinal fluid ( CSF ) flow . We established and partially characterized two immortalized cell lines generated from primary rat arachnoid cells , using retroviral gene transfer of SV40 large T antigen ( SV40 LTAg ) either with or without human telomerase ( hTERT ) . The established cell lines stably express either SV40 LTAg alone , or SV40 LTAg and hTERT , and demonstrate high proliferative rate , contact inhibition at confluence , and stable expression of protein markers characteristic of native arachnoid cells over more than 160 passages . OUTPUT:

enabling replicative immortality;evading growth suppressors

HoC_dynamic_1_shot163

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: AIM To investigate whether luteolin , a highly prevalent flavonoid , reverses the effects of epithelial-mesenchymal transition ( EMT ) in vitro and in vivo and to determine the mechanisms underlying this reversal . METHODS Murine malignant melanoma B16F10 cells were exposed to 1% O(2) for 24 h . Cellular mobility and adhesion were assessed using Boyden chamber transwell assay and cell adhesion assay , respectively . EMT-related proteins , such as E-cadherin and N-cadherin , were examined using Western blotting . Female C57BL/6 mice ( 6 to 8 weeks old ) were injected with B16F10 cells ( 1�10(6) cells in 0.2 mL per mouse ) via the lateral tail vein . The mice were treated with luteolin ( 10 or 20 mg/kg , ip ) daily for 23 d . On the 23rd day after tumor injection , the mice were sacrificed , and the lungs were collected , and metastatic foci in the lung surfaces were photographed . Tissue sections were analyzed with immunohistochemistry and HE staining . RESULTS Hypoxia changed the morphology of B16F10 cells in vitro from the cobblestone-like to mesenchymal-like strips , which was accompanied by increased cellular adhesion and invasion . Luteolin ( 5-50 μmol/L ) suppressed the hypoxia-induced changes in the cells in a dose-dependent manner . Hypoxia significantly decreased the expression of E-cadherin while increased the expression of N-cadherin in the cells ( indicating the occurrence of EMT-like transformation ) , which was reversed by luteolin ( 5 μmol/L ) . In B16F10 cells , luteolin up-regulated E-cadherin at least partly via inhibiting the β3 integrin/FAK signal pathway . In experimental metastasis model mice , treatment with luteolin ( 10 or 20 mg/kg ) reduced metastatic colonization in the lungs by 50% . Furthermore , the treatment increased the expression of E-cadherin while reduced the expression of vimentin and β3 integrin in the tumor tissues . CONCLUSION Luteolin inhibits the hypoxia-induced EMT in malignant melanoma cells both in vitro and in vivo via the regulation of β3 integrin , suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent . OUTPUT: activating invasion and metastasis INPUT: Melanoma cells express and interact with laminins ( LMs ) and other basement membrane components during invasion and metastasis . In the present study we have investigated the production and migration-promoting activity of laminin isoforms in melanoma . Immunohistochemistry of melanoma specimens and immunoprecipitation/western blotting of melanoma cell lines indicated expression of laminin-111/121 , laminin-211 , laminin-411/421 , and laminin-511/521 . Laminin-332 was not detected . In functional assays , laminin-111 , laminin-332 , and laminin-511 , but not laminin-211 and laminin-411 , strongly promoted haptotactic cell migration either constitutively or following stimulation with insulin-like growth factors . Both placenta and recombinant laminin-511 preparations were highly active , and the isolated recombinant IVa domain of LMα5 also promoted cell migration . Function-blocking antibodies in cell migration assays revealed α6β1 integrin as the major receptor for laminin-111 , and both α3β1 and α6β1 integrins for laminin-332 and laminin-511 . In contrast , isolated LMα5 IVa domain-promoted melanoma cell migration was largely mediated via αVβ3 integrin and inhibited by RGD peptides . Given the ubiquitous expression of α5 laminins in melanoma cells and in melanoma-target tissues/anatomical structures , as well as the strong migration-promoting activity of these laminin isoforms , the α5 laminins emerge as putative primary extracellular matrix mediators of melanoma invasion and metastasis via α3β1 and other integrin receptors . OUTPUT:

sustaining proliferative signaling;activating invasion and metastasis

HoC_dynamic_1_shot164

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Single-nucleotide polymorphisms in genes involved in DNA-damage-induced responses are reported frequently to be a risk factor in various cancer types . Here we analysed polymorphisms in 5 genes involved in DNA repair ( XPD Asp312Asn and Lys751Gln , XRCC1 Arg399Gln , APE1 Asp148Glu , NBS1 Glu185Gln , and XPA G-4A ) and in a gene involved in regulation of the cell-cycle ( CCND1 A870G ) . We compared their frequencies in groups of colon , head and neck , and breast cancer patients , and 2 healthy control groups : ( 1 ) matched healthy Polish individuals and ( 2 ) a NCBI database control group . Highly significant differences in the distribution of genotypes of the APE1 , XRCC1 and CCND1 genes were found between colon cancer patients and healthy individuals . The 148Asp APE1 allele and the 399Gln XRCC1 allele apparently increased the risk of colon cancer ( OR = 1.9-2.3 and OR = 1.5-2.1 , respectively ) . Additionally , frequencies of XPD genotypes differed between healthy controls and patients with colon or head and neck cancer . Importantly , no differences in the distribution of these polymorphisms were found between healthy controls and breast cancer patients . The data clearly indicate that the risk of colon cancer is associated with single-nucleotide polymorphism in genes involved in base-excision repair and DNA-damage-induced responses . OUTPUT: evading growth suppressors;genomic instability and mutation INPUT: DNA repair enzymes play an important role in the development of various kinds of cancer . We here analyzed associations of XPD Lys751Gln , APEX1 Asp148Glu , XRCC1 Arg399Gln , and XRCC3 Thr241Met gene polymorphisms in DNA repair pathways in relation to the risk of lung cancer using PCR-RFLP . The study involved 104 lung cancer patients and 120 non-cancer controls divided into non-smokers and smokers . We found a statistically significant interaction between APEX1 Asp148Glu and the risk for lung cancer ( adjusted OR 2.78 , 95% CI 1.58-4.90 , p=0.0004 ) , of both adenocarcinoma ( adjusted OR 2.24 , 95%CI 1.18-4.25 , p=0.014 ) and squamous cell carcinoma ( adjusted OR 4.75 , 95%CI 1.79-12.6 , p=0.002 ) types . XRCC1 Arg399Gln showed a borderline significant association with adenocarcinoma ( adjusted OR 1.89 , 95%CI 1.00-3.57 , p=0.051 ) . The combined effect of smoking and presence of the APEX1 Asp148Glu demonstrated a significant association with risk of lung cancer ( adjusted OR 3.61 , 95% CI 1.74-7.50 , p=0.001 ) . The XPD Lys751Gln and XRCC3 Thr241Met genotypes displayed no statistically significant risk . Our findings suggest that the APEX1 Asp148Glu is associated with increased risk for primary lung cancer in Japanese individuals partaking in smoking . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot165

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Inflammation which is an indispensable participant in tumor progression is intricately linked with redox modulation . The pro-inflammatory cytokine Tumor Necrosis Factor ( TNFalpha ) elevates reactive oxygen species ( ROS ) in glioblastoma multiforme ( GBM ) . As both TNFalpha and oxidative stress independently play role in regulating cytoskeletal organization and cell survival pathways we investigated whether TNFalpha mediated oxidative stress regulates responses that offer survival advantages to glioblastoma cells . Treatment with TNFalpha elevated Akt phosphorylation in glioma cells . Increased in Akt phosphorylation was concurrent with the decrease in ROS scavenger SOD-1 levels . TNFalpha mediated increase in Akt phosphorylation was dependent on oxidative stress as Akt phosphorylation was abrogated in the presence of ROS inhibitor and elevated in cells transfected with SOD-1 siRNA . TNFalpha altered actin cytoskeletal organization and increased Cdc42 levels . This increase in Cdc42 was concomitant with its increased interaction with scaffold protein IQGAP-1 . Also , we report for the first time a ROS dependent interaction between pAkt and IQGAP-1 in TNFalpha treated cells . Importantly , Akt inhibition not only reversed TNFalpha mediated changes in actin cytoskeletal organization but also abrogated anchorage independent growth . Together , these results suggest that TNFalpha induced oxidative stress affects Akt activation to regulate actin organization and growth of glioma cells . OUTPUT: tumor promoting inflammation INPUT: BACKGROUND NFκB signaling is of paramount importance in the regulation of apoptosis , proliferation , and inflammatory responses during human development and homeostasis , as well as in many human cancers . Receptor Tyrosine Kinases ( RTKs ) , including the Fibroblast Growth Factor Receptors ( FGFRs ) are also important in development and disease . However , a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described , although FGFs have been known to antagonize TNFα-induced apoptosis . METHODOLOGY/PRINCIPAL FINDINGS Here , we demonstrate an interaction between FGFR4 and IKKβ ( Inhibitor of NFκB Kinase β subunit ) , an essential component in the NFκB pathway . This novel interaction was identified utilizing a yeast two-hybrid screen [ 1 ] and confirmed by coimmunoprecipitation and mass spectrometry analysis . We demonstrate tyrosine phosphorylation of IKKβ in the presence of activated FGFR4 , but not kinase-dead FGFR4 . Following stimulation by TNFα ( Tumor Necrosis Factor α ) to activate NFκB pathways , FGFR4 activation results in significant inhibition of NFκB signaling as measured by decreased nuclear NFκB localization , by reduced NFκB transcriptional activation in electophoretic mobility shift assays , and by inhibition of IKKβ kinase activity towards the substrate GST-IκBα in in vitro assays . FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity , concomitant reduction in NFκB nuclear localization , and reduced apoptosis . Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells , in comparison with TNFα alone , favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling . CONCLUSIONS/SIGNIFICANCE These results identify a compelling link between FGFR4 signaling and the NFκB pathway , and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling . We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot166

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Radiation-induced carcinogenesis is a major concern both for astronauts on long-term space missions and for cancer patients being treated with therapeutic radiation . Exposure to radiation induces oxidative stress and chronic inflammation , which are critical initiators and promoters of carcinogenesis . Many studies have demonstrated that non-steroidal anti-inflammatory drugs and antioxidants can reduce the risk of radiation-induced cancer . In this study , we found that a synthetic triterpenoid , CDDO-Me ( bardoxolone methyl ) , was able to protect human colon epithelial cells ( HCECs ) against radiation-induced transformation . HCECs that were immortalized by ectopic expression of hTERT and cdk4 and exhibit trisomy for chromosome 7 ( a non-random chromosome change that occurs in 37% of premalignant colon adenomas ) can be transformed experimentally with one combined exposure to 2 Gy of protons at 1 GeV/nucleon followed 24 h later by 50 cGy of ( 56)Fe ions at 1 GeV/nucleon . Transformed cells showed an increase in proliferation rate and in both anchorage-dependent and independent colony formation ability . A spectrum of chromosome aberrations was observed in transformed cells , with 40% showing loss of 17p ( e.g. loss of one copy of p53 ) . Pretreatment of cells with pharmacological doses of CDDO-Me , which has been shown to induce antioxidative as well as anti-inflammatory responses , prevented the heavy-ion-induced increase in proliferation rate and anchorage-dependent and independent colony formation efficiencies . Taken together , these results demonstrate that experimentally immortalized human colon epithelial cells with a non-random chromosome 7 trisomy are valuable premalignant cellular reagents that can be used to study radiation-induced colorectal carcinogenesis . The utility of premalignant HCECs to test novel compounds such as CDDO-Me that can be used to protect against radiation-induced neoplastic transformation is also demonstrated . OUTPUT: genomic instability and mutation;tumor promoting inflammation INPUT: By using the rat azoxymethane ( AOM)-induced colon carcinogenesis model , which mirrors many clinical features of human colorectal cancer , we examined whether genetic changes occurring early in colonic mucosa are predictive of treatment efficacy . In the present study the administration of the chemopreventive agent lupulone over the course of 7 weeks postinitiation reduced the number of preneoplastic lesions in the colonic mucosa by 50% . At the molecular level we observed the downregulation of genes involved in the inflammatory response , including IL-1β and TNF-α , and of matrix metalloproteinase-7 gene and protein expression . We also observed a substantial upregulation of components of the innate immune system , α-defensin-5 and lipocalin 2 . Lupulone induced the expression of apoptosis-related genes and caused a reversal of the B-cell lymphoma/leukemia 2 ( Bcl-2 ; antiapoptotic ) to Bcl-2 associated X protein ( Bax ; proapoptotic ) transcript and protein ratios ( Bcl-2/Bax &gt ; 1 in AOM controls and Bcl-2/Bax &lt ; 1 in lupulone-treated AOM rats ) . Here , we identify several target genes that could be considered early biomarkers of colon carcinogenesis and indicative of drug efficacy . OUTPUT:

tumor promoting inflammation;resisting cell death

HoC_dynamic_1_shot167

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Polymorphisms in DNA repair genes are associated with ability to remove DNA lesions , and therefore may contribute to an individual's susceptibility to different types of cancer . Base excision repair ( BER ) , and nucleotide excision repair ( NER ) are the main DNA repair pathways . The present study was conducted to determine the frequency distribution of single nucleotide polymorphisms ( SNPs ) selected for genes in these two pathways i.e . OGG1 Exon 7 ( C1245G ) , XPC Intron 9 ( PAT ) , and Exon 15 ( A33512C ) in a North Indian population in comparison with global populations . METHODS Genotyping was achieved by PCR-based analysis in 224 normal healthy , unrelated individuals of similar ethnicity . RESULTS Allelic frequencies in wild type of OGG1 Exon 7 C>G were 73% ( C ) ; XPC PAT D>I 75% ( D ) ; and XPC Exon 15 A>C 60.71.9% A. On the other hand , the variant allele frequency were 27% ( G ) in OGG1 Exon 7 C>G ; 25% ( I ) in XPC PAT ; and 28.1% ( C ) in XPC Exon 15 A>C . Major differences from other ethnic populations were observed . CONCLUSIONS Our results suggest that frequency distribution in these DNA repair genes exhibited a distinctive pattern in our population which could be attributed to ethnic variation . This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups . OUTPUT: genomic instability and mutation INPUT: Background : Several polymorphisms in the DNA repair gene have been extensively studied in the association with various human cancers such as breast cancer . Material and methods : We investigated the association of polymorphisms in the DNA repair genes XRCC1-Arg399Gln , XRCC2-Arg188His and RAD51-135G/C with the breast cancer risk . Genotypes were determined by PCR-RFLP assays in 220 patients with breast cancer and 220 age-matched healthy controls . Results : Our results demonstrated a significant positive association between the XRCC1 399Gln/Gln homozygous genotype and breast carcinoma , with an adjusted odds ratio ( OR ) of 2.08 [ 1.08-3.98 ] . The 399Gln allele variant was also associated with type I breast cancer ( OR = 1.41 [ 0.98-2.01 ] , p = 0.034 ) . The distributions of genotypes and alleles of the genes XRCC2 and RAD51 polymorphism were not significantly associated with the different stages of breast carcinoma ( p &gt ; 0.05 ) . Conclusion : These results suggest that 399Gln allele of XRCC1 Arg399Gln may be a risk factor for breast cancer in the Polish population . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot168

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Non-small cell lung cancer ( NSCLC ) , accounting for 80% of lung cancers , is the leading cause of all cancer deaths . Previously , we demonstrated that delta-tocotrienol inhibits NSCLC cell proliferation , invasion and induces apoptosis by down-regulation of the Notch-1 signaling pathway . The objective of this study was to investigate whether delta-tocotrienol , could enhance the anticancer effects of cisplatin . Treatment with a combination of delta-tocotrienol and cisplatin resulted in a dose-dependent , significant inhibition of cell growth , migration , invasiveness , and induction of apoptosis in NSCLC cells , as compared to the single agents . This was associated with a decrease in NF-κB DNA binding activity , decrease in Notch-1 , Hes-1 , Bcl-2 and increase in cleaved Caspase-3 and PARP expressions . These results suggest that down-regulation of Notch-1 , via inhibition of NF-κB signaling pathways by delta-tocotrienol and cisplatin , in combination , could provide a potential novel approach for tumor arrest in NSCLC , while lowering the effective dose of cisplatin . OUTPUT: activating invasion and metastasis;resisting cell death;sustaining proliferative signaling INPUT: OBJECTIVES Despite the well-defined histological types of non-small cell lung cancer ( NSCLC ) , a given stage is often associated with wide-ranging survival rates and treatment outcomes . This disparity has led to an increased demand for the discovery and identification of new informative biomarkers . METHODS In the current study , we screened 81 NSCLC samples using Illumina whole-genome gene expression microarrays in an effort to identify differentially expressed genes and new NSCLC biomarkers . RESULTS We identified novel genes whose expression was upregulated in NSCLC , including SPAG5 , POLH , KIF23 , and RAD54L , which are associated with mitotic spindle formation , DNA repair , chromosome segregation , and dsDNA break repair , respectively . We also identified several novel genes whose expression was downregulated in NSCLC , including SGCG , NLRC4 , MMRN1 , and SFTPD , which are involved in extracellular matrix formation , apoptosis , blood vessel leakage , and inflammation , respectively . We found a significant correlation between RNA degradation and survival in adenocarcinoma cases . CONCLUSIONS Even though the follow-up time was too limited to draw final conclusions , we were able to show better prediction p values in a group selection based on molecular profiles compared to histology . The current study also uncovered new candidate biomarker genes that are likely to be involved in diverse processes associated with NSCLC development . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot169

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands . Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects . It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function . In an effort to recapitulate the effects of IGF-1 , as well as increase the likelihood of translating these findings to the clinic , the small molecule therapeutic Roscovitine , is being tested . Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues . METHODOLOGY/PRINCIPAL FINDINGS Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2)/M phase , as demonstrated by flow cytometry . In contrast , mice treated with radiation exhibit no differences in the percentage of cells in G(2)/M when compared to unirradiated controls . Similar to previous studies utilizing IGF-1 , pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells . Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells , which is suppressed by pretreatment with Roscovitine . Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands , both acutely and chronically , as measured by salivary output . CONCLUSIONS/SIGNIFICANCE These studies suggest that induction of transient G(2)/M cell cycle arrest by Roscovitine allows for suppression of apoptosis , thus preserving normal salivary function following targeted head and neck irradiation . This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues . OUTPUT: sustaining proliferative signaling;resisting cell death INPUT: Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands . Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects . It has been previously shown in mice expressing a constitutively active form of Akt ( myr-Akt1 ) , or in mice pretreated with IGF1 , apoptosis is suppressed , which correlates with maintained salivary gland function measured by stimulated salivary flow . Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair . We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1 . As p21 , a transcriptional target of the p53 family , is necessary for maintaining G2/M arrest , we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression . Pretreatment with IGF1 reduces binding of ΔNp63 to the p21 promoter after irradiation , which coincides with increased p53 binding and sustained p21 transcription . Our data indicate a role for ΔNp63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated . OUTPUT:

evading growth suppressors;sustaining proliferative signaling

HoC_dynamic_1_shot170

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Stannous chloride ( SnCl(2) ) and UVA induce DNA lesions through ROS . The aim of this work was to study the toxicity induced by UVA preillumination , followed by SnCl(2) treatment . E. coli BER mutants were used to identify genes which could play a role in DNA lesion repair generated by these agents . The survival assays showed ( i ) The nfo mutant was the most sensitive to SnCl(2) ; ( ii ) lethal synergistic effect was observed after UVA pre-illumination , plus SnCl(2) incubation , the nfo mutant being the most sensitive ; ( iii ) wild type and nfo mutants , transformed with pBW21 plasmid ( nfo(+) ) had their survival increased following treatments . The alkaline agarose gel electrophoresis assays pointed that ( i ) UVA induced DNA breaks and fpg mutant was the most sensitive ; ( ii ) SnCl(2)-induced DNA strand breaks were higher than those from UVA and nfo mutant had the slowest repair kinetics ; ( iii ) UVA + SnCl(2) promoted an increase in DNA breaks than SnCl(2) and , again , nfo mutant displayed the slowest repair kinetics . In summary , Nfo protects E. coli cells against damage induced by SnCl(2) and UVA + SnCl(2) . OUTPUT: genomic instability and mutation INPUT: Ultraviolet ( UV ) of sunlight is a complete carcinogen that can burn skin , enhance inflammation , and drive skin carcinogenesis . Previously , we have shown that sulforaphane ( SFN ) inhibited chemically induced skin carcinogenesis via nuclear factor ( erythroid-derived 2)-like 2 ( Nrf2 ) and others have shown that broccoli sprout extracts containing high SFN protected against UV-induced skin carcinogenesis in SKH-1 hairless mice . A recent study showed that there was no difference between Nrf2 knockout ( Nrf2 KO ) and Nrf2 wild-type ( WT ) BALB/C mice after exposing to high dose of UVB . Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses , it is relevant to assess the role of Nrf2 for photoprotection against UV . In this context , the role of Nrf2 in UVB-induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was studied . A single dose of UVB ( 300 mJ/cm(2) ) resulted in skin inflammation in both WT and Nrf2 KO ( -/- ) mice ( KO mice ) at 8 h and 8 d following UVB irradiation . In the WT mice inflammation returned to the basal level to a greater extent when compared to the KO mice . SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation . Additionally , UVB-induced short-term inflammatory biomarkers ( interleukin-1β and interleukin-6 ) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT . Taken together , our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation , sunburn reaction , and SFN-mediated photoprotective effects in the skin . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot171

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Alterations of the epidermal growth factor receptor ( EGFR ) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7 . We have previously shown that this mutant receptor , called DeltaEGFR , confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo . To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation , we examined the gene products that control cell cycle progression . We found that levels of the cyclin-dependent kinase ( CDK ) inhibitor , p27 , were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors . Consequently , CDK2-cyclin A activity was also elevated , concomitant with the RB protein hyperphosphorylation . In addition , activated phosphatidylinositol 3-kinase ( PI3-K ) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors . U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB . Treatment of U87MG.DeltaEGFR cells with LY294002 , a PI3-K inhibitor , caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27 . Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo . These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway . This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: We recently isolated an exon-4-deleted epidermal growth factor receptor ( EGFR ) variant , termed de4 EGFR . Because the extracellular domain alteration of receptors often influences the antitumor effect of therapeutic antibodies , it is essential to test the sensitivity of de4 EGFR(+) tumors to anti-EGFR antibodies . Therefore , in this study , the antitumor activities of mAb CH12 , an anti-EGFRvIII antibody developed in our laboratory , as well as a U.S. Food and Drug Administration-approved anti-EGFR antibody , cetuximab ( C225 ) , were characterized on de4 EGFR(+) models . The results of FACS assays showed that CH12 bound to de4 EGFR with a higher avidity than did C225 . Interestingly , CH12 , but not C225 , significantly inhibited the metastasis and growth of U87MG-de4 EGFR xenografts , with a growth-inhibition ratio of 46.48% in vivo , and prolonged the survival of the tumor-bearing mice by 37.2% . Treatment with CH12 significantly suppressed tumor proliferation and angiogenesis with increased tumor apoptosis . Mechanistically , de4 EGFR protein expression was virtually undetectable in the U87MG-de4 EGFR xenografts treated with CH12 . This may account for the observed reduction of Akt and Erk phosphorylation , cyclin D1 , Bcl-2 , and Bcl-x(L) expression and the increase of p27 and E-cadherin expression . Intriguingly , LAMP-1 , a major component of the lysosome , was significantly up-regulated in the CH12-treated group but not in the C225-treated group , suggesting its contribution to the degradation of de4 EGFR . Taken together , our data demonstrated that mAb CH12 is a promising therapeutic agent for treating de4 EGFR(+) gliomas . OUTPUT:

activating invasion and metastasis;inducing angiogenesis;resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot172

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Androgens and the androgen receptor ( AR ) play important roles in the development of male urogenital organs . We previously found that mice with total AR knockout ( ARKO ) and epithelial ARKO failed to develop normal prostate with loss of differentiation . We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate . However , AR roles of stromal fibroblasts in prostate development remain unclear . METHODS To further probe the stromal fibroblast AR roles in prostate development , we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts ( FSP-ARKO ) . We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development . RESULTS The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation , increased apoptosis , and decreased collagen composition . Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors . To further confirm these in vivo findings , we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells , as well as decrease of some stromal growth factors . CONCLUSIONS Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate , but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: Endothelin plays important roles in various physiological functions including vascular constriction . Recent studies reported that the endothelin receptors ETA and ETB are highly expressed in lung and skin tumor tissues . In contrast , there are few reports on endothelin signalling in the proliferation of head and neck cancer . We found that both ETA and ETB endothelin receptors were overexpressed in tumor cells of tongue cancer samples by immunohistochemistry . ETA and ETB were expressed in cultured lingual and esophageal squamous cell carcinoma ( SCCs ) cell lines . When both cultured cell lines were treated with an ETA selective antagonist ( BQ123 ) or an ETB selective antagonist ( BQ788 ) , inhibition of cell growth was observed . Similar results were observed when SCCs were treated with specific siRNA for the suppression of ETA or ETB . Furthermore , inhibition of the mitogen-activated protein ( MAP ) kinase pathway by the treatments with ET receptor antagonists and siRNA was also observed . These results indicate that endothelin signalling may , in part , play important roles in cell growth in SCCs through the MAP kinase pathway . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot173

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND Tissue factor ( TF ) , an initiator of blood coagulation , participates in cancer progression and metastasis . We recently found that inhibition of MAPK/ERK upregulated both full length TF ( flTF ) and soluble isoform TF ( asTF ) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells . We explored the possible mechanisms , especially the possible interaction with EGFR and PI3K/Akt pathways . METHODS A plasmid containing TF promoter -2174  plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity . In order to study the interaction of these pathways , ERK inhibitor ( PD98059 ) , PI3K inhibitors ( LY294002 , wortmannin ) , Akt inhibitor ( A6730 ) , and EGFR inhibitor ( erlotinib ) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells , and ovarian cancer OVCAR-3 and SKOV-3 cells . Quantitative PCR and western blot were used to determine TF expression . One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells . RESULTS We show that PI3K inhibitors LY294002 , wortmannin and A6730 significantly inhibited TF promoter activity , and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation . In contrast , ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells . The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors . Most interestingly , the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression . Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3 . Furthermore , in MDA-MB-231 , mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment . CONCLUSIONS This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells . The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells . Interestingly , we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231 . As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells , targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression . OUTPUT: sustaining proliferative signaling INPUT: Pancreatic cancer remains the fourth most common cause of cancer-related death in the United States . Potent therapeutic strategies are urgently needed for pancreatic cancer . Cucurmosin is a novel type1 ribosome-inactivating protein ( RIP ) isolated from the sarcocarp of Cucurbita moschata ( pumpkin ) . Due to its cytotoxicity , cucurmosin can inhibit tumor cell proliferation through induction of apoptosis on tumor cells , but the specific mechanism is still unclear . We explored the function of cucurmosin in BxPC-3 pancreatic cancer cells using multiple cellular and molecular approaches such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay , flow cytometry , reverse transcription polymerase chain reaction ( RT-PCR ) , Western blotting and transmission electron microscopy for observing typical changes and formation of apoptotic bodies . We found that cucurmosin inhibited the proliferation of BxPC-3 cells in a time- and dose-dependent manner , and increased the cell population in the G0-G1 phase . With increasing concentration of cucurmosin , the expression of EGFR , p-PI3K , Akt , p-Akt , mTOR , p-mTOR , P70S6K-α , p-P70S6K-α , 4E-BP1 and p-4E-BP1 at the protein level was decreased , whereas the expression of p-Bad and caspase-9 was elevated . However , the mRNA expression of EGFR did not change . These findings suggest that cucurmosin can down-regulate the expression of EGFR by targeting . Cucurmosin induces the apoptosis of BxPC-3 pancreatic cancer cells via the PI3K/Akt/mTOR signaling pathway . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot174

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Mesenchymal stem cells ( MSCs ) are generally used in tissue engineering , regenerative medicine and therapy for immune disorder disease . MSCs are also employed as drug carriers for tumor therapy due to their ability to migrate to tumor tissue . However , due to the immunosuppressive function of MSCs , the application of MSCs in prostate cancer therapy remains limited . In this study , we investigated the underlying mechanism by which MSCs enable prostate cancer cells to escape from immune surveillance in the inflammatory microenvironment . Firstly , we demonstrated that compared with the control groups , MSCs pretreated with IL-1α effectively promoted the growth of the mouse prostate cancer cell line RM-1 invivo . Furthermore , when RM-1 prostate cancer cells were co-injected with MSCs pretreated with IL-1α , tumor incidence significantly increased in allogeneic recipients . In addition , we investigated the mechanism through which MSCs promote the ability of RM-1 cells to escape from immune injury . The results revealed that IL-1α led to the upregulation of TGF-β in MSCs . The inflammatory cytokine-induced promotive effect of MSCs on RM-1 cells in vivo was inhibited by TGF-β siRNA . The results of our study suggest that inflammatory cytokines induce the immunosuppressive function of MSCs which enables prostate cancer cells to escape from immune injury . OUTPUT: sustaining proliferative signaling;tumor promoting inflammation;avoiding immune destruction INPUT: Previous studies have demonstrated that mesenchymal stromal cells ( MSCs ) enhance cell survival through upregulation and secretion of stanniocalcin-1 ( STC1 ) . This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation , reducing intracellular reactive oxygen species ( ROS ) , and shifting metabolism towards a more glycolytic metabolic profile . MSC-derived STC1 upregulated uncoupling protein 2 ( UCP2 ) in injured A549 cells in an STC1-dependent manner . Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 ( rSTC1 ) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS , mitochondrial membrane potential ( MMP ) , and increased lactate production , all of which were dependent on the upregulation of UCP2 . Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1 . OUTPUT:

cellular energetics;tumor promoting inflammation

HoC_dynamic_1_shot175

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND AND AIM The importance of glycolysis in cancer cells is well documented . The effects of inhibiting glycolysis using metabolic inhibitors iodoacetate ( IAA ) , an inhibitor of GAPDHase , and 3-bromopyruvate ( 3BP ) , an inhibitor of hexokinase-II , on survival and signaling of pancreatic cancer cells ( Panc-1 ) were investigated . MATERIALS AND METHODS Cellular survival was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ( MTT ) assay . Lactate dehydrogenase ( LDH ) assay was used to analyze the induced necrosis and protein levels were evaluated using Western blot analysis . RESULTS The results show that the inhibitors lowered cellular survival and increased cellular necrosis . Mitogenic signaling pathways were affected by 3BP but not by IAA . CONCLUSION We conclude that there may be a cross-talk between signaling pathways and glycolysis in regulating pancreatic cancer cell survival and signaling . Thus , a combination of agents that inhibit both energy production and cell signaling may provide a novel and effective approach to target pancreatic cancer effectively . OUTPUT: resisting cell death;cellular energetics INPUT: Recent evidences suggest that the activity of glycogen synthase kinase-3 ( GSK3 ) contributes to the tumorigenic potential of pancreatic cancer cells through modulation of cell proliferation and survival . However , further investigations are needed to identify GSK3-dependent mechanisms involved in the control of pancreatic cancer cell proliferation and survival . This study was undertaken to provide further support for a role of GSK3 in pancreatic cancer cell growth as well as to identify new cellular and molecular mechanisms involved . Herein , we demonstrate that prolonged inhibition of GSK3 triggers an apoptotic response only in human pancreatic cancer cells but not in human non-transformed pancreatic epithelial cells . We show that prolonged inhibition of GSK3 activity increases Bim messenger RNA and protein expressions . Moreover , we provide evidence that activation of the c-jun N-terminal kinase ( JNK ) pathway is necessary for the GSK3 inhibition-mediated increase in Bim expression and apoptotic response . Finally , we demonstrate that concomitant inhibition of GSK3 potentiates the death ligand-induced apoptotic response in pancreatic cancer cells but not in non-transformed pancreatic epithelial cells and that this effect also requires JNK activity . Considering that different approaches leading to stimulation of death receptor signaling are under clinical trials for treatment of unresectable or metastatic pancreatic cancer , inhibition of GSK3 could represent an attractive new avenue to improve their effectiveness . OUTPUT:

resisting cell death

HoC_dynamic_1_shot176

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The Ras association domain family 1 isoform A ( RASSF1A ) is a tumor suppressor whose inactivation is implicated in the development of many human cancers , including breast carcinomas . Little is known about the tumor-suppressive function of RASSF1A in breast tissue and whether its inactivation is mechanistically involved in the initiation and progression of breast tumors . Here , we show that RASSF1A inhibits breast cancer growth in vivo , and suppresses estrogen receptor ( ERα ) expression and function . Reconstitution of RASSF1A in MCF7 cells led to decreased ERα levels and reduced sensitivity to estrogen ( E2 ) . Concomitantly , we observed decreased expression of Id1 as well as the E2-responsive genes Bcl-2 and c-Myc that cooperatively contribute to the immortalization and transformation of breast epithelial cells . This downregulation was associated with induction of cell-cycle arrest and senescence that constitute early barriers to cancer initiation and progression . Knockdown of ERα showed that downregulation of ERα suffices to increase senescence and inhibit expression of Bcl-2 , c-Myc and Id1 . However , enforced expression of ERα only partially rescued RASSF1A-mediated growth inhibition and senescence , suggesting that suppression of ERα expression and activity is not the only mechanism by which RASSF1A inhibits growth and survival of breast cancer cells . Ectopic expression of Bcl-2 , c-Myc and Id1 had little or no effect on RASSF1A-mediated growth arrest , indicating that RASSF1A acts dominantly over these oncogenes . Mechanistically , RASSF1A was found to suppress ERα expression through Akt1 . It also transiently inhibited ERα-induced Ras-MAPK activity after exposure of cells to E2 . Together , our data show that RASSF1A acts as a tumor suppressor in ERα+ mammary epithelial cells , in part through inhibiting ERα expression and activity . These findings suggest that RASSF1A has a key role in suppressing the transformation of human breast epithelial cells and ERα+ breast cancer initiation . OUTPUT: sustaining proliferative signaling;enabling replicative immortality INPUT: BACKGROUND The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions . The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition . The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy . RESULTS Here , we report that Ron expression is correlated with in situ , estrogen receptor alpha ( ERα)-positive tumors , and is higher in breast tumors following neoadjuvant tamoxifen therapy . We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression ( MMTV-Ron mice ) , exhibit appreciable ER expression . Moreover , genetic-ablation of ERα , in the context of Ron overexpression , leads to delayed mammary tumor initiation and growth , but also results in an increased metastasis . CONCLUSIONS Ron receptor overexpression is associated with ERα-positive human and murine breast tumors . In addition , loss of ERα on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERα , as in the case of tamoxifen therapy , may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic . OUTPUT:

sustaining proliferative signaling;activating invasion and metastasis

HoC_dynamic_1_shot177

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: To investigate whether the Bcl-2 gene family is involved in modulating mechanism of apoptosis and change of cell cycle protein induced by curcumin in acute myeloid leukemia HL-60 cell line and primary acute myelogenous leukemic cells , the Bcl-2 family member Mcl-1 , Bax and Bak and cell cycle proteins including P27kipl , P21wafl , cyclin D3 and pRbp- were selected and their expression detected by SABC immuno-histochemical stain method . The attitude of sub-G1 peak in DNA histogram was determined by FCM . The TUNEL positive cell percentage was identified by terminal deoxynucleotidyl transferase ( TdT)-mediated Biotin dUNP end labeling technique . It was found that when HL-60 cells were treated with 25 mumol/L curcumin for 24 h , the expression level of Mcl-1 was down-regulated , but that of Bax and Bak up-regulated time-dependently . There was significant difference in the expression level of Mcl-1 , Bax and Bak between the curcumin-treated groups and control group ( P &lt ; 0.05-0.01 ) . At the same time , curcumin had no effect on progress of cell cycle in primaty acute myelogenous leukemia at newly diagnosis , but could increase the peak of Sub-G1 ( P &lt ; 0.05 ) , and down-regulate the expression of Mcl-1 and up-regulate the expression of Bax and Bak with the difference being statistically significant . The expression of P27kipl , P21wafl and pRbp- were elevated and that of cyclin D3 decreased in the presence of curcumin . These findings suggested that the Bcl-2 gene family indeed participated in the regulatory process of apoptosis induced by curcumin in HL-60 cells and AML cells . Curcumin can induce apoptosis of primary acute myelogenous leukemic cells and disturb cell cycle progression of HL-60 cells . The mechanism appeared to be mediated by perturbing G0/G1 phases checkpoints which associated with up-regulation of P27kipl , P21wafl and pRbp- expression , and down-regulation of cyclin D3 . OUTPUT: sustaining proliferative signaling;evading growth suppressors;resisting cell death INPUT: Chronic myelogenous leukemia ( CML ) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein . Clinically , CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis . A CML-specific immune response is thought to contribute to the control of disease . Whether the immune system can also promote disease progression is not known . In the present study , we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells ( LSCs ) and mediates effects of the immune system on CML . In a mouse model of CML , BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27 . Binding of CD27 by its ligand , CD70 , increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active β-catenin and TRAF2- and NCK-interacting kinase ( TNIK ) . This resulted in increased proliferation and differentiation of LSCs . Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival . Furthermore , CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients , and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway . Since expression of CD70 is limited to activated lymphocytes and dendritic cells , our results reveal a mechanism by which adaptive immunity contributes to leukemia progression . In addition , targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/β-catenin pathway in CML . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot178

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Various endocrine disrupting chemicals ( EDCs ) are exogenous compounds found in the environment and have the potential to interfere with the endocrine system and hormonal regulation . Among EDCs , bisphenolA ( BPA ) and 1,1,1-trichloro-2,2-bis(4-methoxyphenol)-ethane [ methoxychlor ( MXC) ] have estrogenic activity resulting in a variety of dysfunctions in the E2-mediated response by binding to estrogen receptors ( ERs ) , causing human health problems such as abnormal reproduction and carcinogenesis . In this study , we investigated the effects of BPA and MXC on cell proliferation facilitated by ER signaling in human breast cancer cells . MCF-7 cells are known to be ERα-positive and to be a highly E2-responsive cancer cell line ; these cells are , therefore , a useful invitro model for detecting estrogenic activity in response to EDCs . We evaluated cancer cell proliferation following BPA and MXC treatment using an MTT assay . We analyzed alterations in the expression of genes associated with the cell cycle in MCF-7 cells by semi-quantitative reverse-transcription PCR following treatment with BPA or MXC compared to EtOH . To determine whether BPA and MXC stimulate cancer cell growth though ER signaling , we co-treated the cells with agonists ( propyl pyrazoletriol , PPT ; and diarylpropionitrile , DPN ) or an antagonist ( ICI 182,780 ) of ER signaling and reduced ERα gene expression via siRNA in MCF-7 cells before treatment with EDCs . These studies confirmed the carcinogenicity of EDCs invitro . As a result , BPA and MXC induced the cancer cell proliferation by the upregulation of genes that promote the cell cycle and the downregulation of anti-proliferative genes , especially ones affecting the G1/S transition via ERα signaling . These collective results confirm the carcinogenicity of these EDCs invitro . Further studies are required to determine whether EDCs promote carcinogenesis invivo . OUTPUT: sustaining proliferative signaling INPUT: Breast cancer is the most common malignancy in women , and many breast cancer patients fail conventional treatment strategies of chemotherapy , radiation , and antiestrogen therapy . Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions . Epidermal growth factor receptor ( EGFR ) and cyclooxygenase-2 ( COX-2 ) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor ( ER ) pathway . Combination of EGFR and COX-2 inhibitors , therefore , could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer . In order to verify the effects of EGFR and COX-2 inhibitors , breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors ( nimotuzumab and celecoxib ) alone and in combination . Both cell lines were sensitive to celecoxib , but not to nimotuzumab . However , combination of two drugs demonstrated synergistic effects on cell killing . Moreover , association of two drugs resulted in SKBR-3 cells , a further G0/G1 phase arrest than one drug alone . Downregulation of p-EGFR , p-Akt , p-mTOR , and amplified in breast cancer 1 ( AIB1 ) were observed in both cell lines , and upregulation of E-cadherin was only found in MCF-7 , after treatment with single agent or in combination . These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer , which partly correlates with ER status . Due to Akt/mTOR , EMT and AIB1 pathways participate in this process , therefore , E-cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot179

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: AIM To investigate whether luteolin , a highly prevalent flavonoid , reverses the effects of epithelial-mesenchymal transition ( EMT ) in vitro and in vivo and to determine the mechanisms underlying this reversal . METHODS Murine malignant melanoma B16F10 cells were exposed to 1% O(2) for 24 h . Cellular mobility and adhesion were assessed using Boyden chamber transwell assay and cell adhesion assay , respectively . EMT-related proteins , such as E-cadherin and N-cadherin , were examined using Western blotting . Female C57BL/6 mice ( 6 to 8 weeks old ) were injected with B16F10 cells ( 1�10(6) cells in 0.2 mL per mouse ) via the lateral tail vein . The mice were treated with luteolin ( 10 or 20 mg/kg , ip ) daily for 23 d . On the 23rd day after tumor injection , the mice were sacrificed , and the lungs were collected , and metastatic foci in the lung surfaces were photographed . Tissue sections were analyzed with immunohistochemistry and HE staining . RESULTS Hypoxia changed the morphology of B16F10 cells in vitro from the cobblestone-like to mesenchymal-like strips , which was accompanied by increased cellular adhesion and invasion . Luteolin ( 5-50 μmol/L ) suppressed the hypoxia-induced changes in the cells in a dose-dependent manner . Hypoxia significantly decreased the expression of E-cadherin while increased the expression of N-cadherin in the cells ( indicating the occurrence of EMT-like transformation ) , which was reversed by luteolin ( 5 μmol/L ) . In B16F10 cells , luteolin up-regulated E-cadherin at least partly via inhibiting the β3 integrin/FAK signal pathway . In experimental metastasis model mice , treatment with luteolin ( 10 or 20 mg/kg ) reduced metastatic colonization in the lungs by 50% . Furthermore , the treatment increased the expression of E-cadherin while reduced the expression of vimentin and β3 integrin in the tumor tissues . CONCLUSION Luteolin inhibits the hypoxia-induced EMT in malignant melanoma cells both in vitro and in vivo via the regulation of β3 integrin , suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND Luteolin is a 3',4',5,7-tetrahydroxyflavone found in various fruits and vegetables . We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest . The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor ( IGF-IR ) signaling pathway in HT-29 cells . METHODS In order to assess the effects of luteolin and/or IGF-I on the IGF-IR signaling pathway , cells were cultured with or without 60 μmol/L luteolin and/or 10 nmol/L IGF-I . Cell proliferation , DNA synthesis , and IGF-IR mRNA levels were evaluated by a cell viability assay , [ 3H]thymidine incorporation assays , and real-time polymerase chain reaction , respectively . Western blot analyses , immunoprecipitation , and in vitro kinase assays were conducted to evaluate the secretion of IGF-II , the protein expression and activation of IGF-IR , and the association of the p85 subunit of phophatidylinositol-3 kinase ( PI3K ) with IGF-IR , the phosphorylation of Akt and extracellular signal-regulated kinase ( ERK)1/2 , and cell division cycle 25c ( CDC25c ) , and PI3K activity . RESULTS Luteolin ( 0 - 60 μmol/L ) dose-dependently reduced the IGF-II secretion of HT-29 cells . IGF-I stimulated HT-29 cell growth but did not abrogate luteolin-induced growth inhibition . Luteolin reduced the levels of the IGF-IR precursor protein and IGF-IR transcripts . Luteolin reduced the IGF-I-induced tyrosine phosphorylation of IGF-IR and the association of p85 with IGF-IR . Additionally , luteolin inhibited the activity of PI3K activity as well as the phosphorylation of Akt , ERK1/2 , and CDC25c in the presence and absence of IGF-I stimulation . CONCLUSIONS The present results demonstrate that luteolin downregulates the activation of the PI3K/Akt and ERK1/2 pathways via a reduction in IGF-IR signaling in HT-29 cells ; this may be one of the mechanisms responsible for the observed luteolin-induced apoptosis and cell cycle arrest . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot180

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cancer cells upregulate glycolysis , increasing glucose uptake to meet energy needs . A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway ( HBP ) , which regulates levels of O-linked beta-N-acetylglucosamine ( O-GlcNAc ) , a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins . We discovered that breast cancer cells upregulate the HBP , including increased O-GlcNAcation and elevated expression of O-GlcNAc transferase ( OGT ) , which is the enzyme catalyzing the addition of O-GlcNAc to proteins . Reduction of O-GlcNAcation through RNA interference of OGT in breast cancer cells leads to inhibition of tumor growth both in vitro and in vivo and is associated with decreased cell-cycle progression and increased expression of the cell-cycle inhibitor p27(Kip1) . Elevation of p27(Kip1) was associated with decreased expression and activity of the oncogenic transcription factor FoxM1 , a known regulator of p27(Kip1) stability through transcriptional control of Skp2 . Reducing O-GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused a decrease in multiple FoxM1-specific targets , including Skp2 . Moreover , reducing O-GlcNAcation decreased cancer cell invasion and was associated with the downregulation of matrix metalloproteinase-2 , a known FoxM1 target . Finally , pharmacological inhibition of OGT in breast cancer cells had similar anti-growth and anti-invasion effects . These findings identify O-GlcNAc as a novel mechanism through which alterations in glucose metabolism regulate cancer growth and invasion and suggest that OGT may represent novel therapeutic targets for breast cancer . OUTPUT: evading growth suppressors;cellular energetics INPUT: Cancer cells universally increase glucose and glutamine consumption , leading to the altered metabolic state known as the Warburg effect ; one metabolic pathway , highly dependent on glucose and glutamine , is the hexosamine biosynthetic pathway . Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translational addition of O-linked β-N-acetylglucosamine ( O-GlcNAc ) to various nuclear and cytosolic proteins . A number of these target proteins are implicated in cancer , and recently , O-GlcNAcylation was shown to play a role in breast cancer ; however , O-GlcNAcylation in other cancers remains poorly defined . Here , we show that O-GlcNAc transferase ( OGT ) is overexpressed in prostate cancer compared with normal prostate epithelium and that OGT protein and O-GlcNAc levels are elevated in prostate carcinoma cell lines . Reducing O-GlcNAcylation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase ( MMP)-2 , MMP-9 , and VEGF , resulting in inhibition of invasion and angiogenesis . OGT-mediated regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1 , a key regulator of invasion and angiogenesis , as reducing OGT expression led to increased FoxM1 protein degradation . Conversely , overexpression of a degradation-resistant FoxM1 mutant abrogated OGT RNAi-mediated effects on invasion , MMP levels , angiogenesis , and VEGF expression . Using a mouse model of metastasis , we found that reduction of OGT expression blocked bone metastasis . Altogether , these data suggest that as prostate cancer cells alter glucose and glutamine levels , O-GlcNAc modifications and OGT levels become elevated and are required for regulation of malignant properties , implicating OGT as a novel therapeutic target in the treatment of cancer . OUTPUT:

activating invasion and metastasis;inducing angiogenesis

HoC_dynamic_1_shot181

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Human papillomavirus type 16 ( HPV16 ) E6 and E7 are selectively retained and expressed in HPV16-associated human genital tumors . E6 is active in several cell culture assays , including transformation of NIH 3T3 cells , trans activation of the adenovirus E2 promoter , and cooperation with E7 to immortalize normal human keratinocytes . Biochemically , the HPV16 E6 protein has been shown to bind to tumor suppressor protein p53 in vitro and induce its degradation in a rabbit reticulocyte lysate . To examine the relationship between the various biological activities of E6 and inactivation of p53 , we tested the abilities of dominant negative mutants of p53 to substitute functionally for E6 in the three cell culture assays . While wild-type p53 inhibited keratinocyte proliferation , both mouse and human mutant p53s , in conjunction with E7 , increased proliferation of the keratinocytes , resulting in generation of immortalized lines . However , in contrast to E6 , mutant p53 was unable to induce transformation or trans activate the adenovirus E2 promoter in NIH 3T3 cells . These results suggest that inactivation of wild-type p53 is necessary for HPV-induced immortalization of human keratinocytes and that different or additional activities are required for E6-dependent transformation and trans activation of NIH 3T3 cells . OUTPUT: enabling replicative immortality INPUT: The NF-kB family of transcription factors regulates important biological functions including cell growth , survival and the immune response . We found that Human Papillomavirus type 16 ( HPV-16 ) E7 and E6/E7 proteins inhibited basal and TNF-alpha-inducible NF-kB activity in human epithelial cells cultured from the cervical transformation zone , the anatomic region where most cervical cancers develop . In contrast , HPV-16 E6 regulated NF-kB in a cell type- and cell growth-dependent manner . NF-kB influenced immortalization of cervical cells by HPV16 . Inhibition of NF-kB by an IkB alpha repressor mutant increased colony formation and immortalization by HPV-16 . In contrast , activation of NF-kB by constitutive expression of p65 inhibited proliferation and immortalization . Our results suggest that inhibition of NF-kB by HPV-16 E6/E7 contributes to immortalization of cells from the cervical transformation zone . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot182

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Epidermal growth factor ( EGF ) receptor is inversely related to expression of estrogen receptor ( ER ) and progesterone receptor in primary breast tumors and is a negative predictor for response to endocrine therapy . To investigate a possible causal role of EGF receptor expression in breast cancer progression to hormone independence , we have created an experimental cell system . Epidermal growth factor receptor complementary DNA was introduced in estrogen-dependent ZR-75-1 breast cancer cells , and the resulting ZR/HERc cells exhibited a mitogenic response to epidermal growth factor , thus bypassing estrogen dependence . This EGF-induced proliferation could not be inhibited by antiestrogens . In addition , we noted changes in cell morphology and keratin expression of EGF-stimulated ZR/HERc cells , suggestive of an altered differentiation state . Furthermore , intolerance of functional ER and EGF receptor signal transduction pathways in ZR/HERc cells was observed during simultaneous activation , which possibly explains the inverse relationship of ER and EGF receptor expression in primary tumors . In contrast to the parental cells , ZR/HERc cells rapidly progressed to a stable ER-negative phenotype when cultured in the presence of the antiestrogen hydroxy-tamoxifen . These results suggest a possible role for EGF receptor in progression of breast cancer to hormone independence . OUTPUT: sustaining proliferative signaling INPUT: High-grade gliomas ( HGG ) , are the most common aggressive brain tumours in adults . Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate . To accurately evaluate response to targeted therapies further in vitro studies are necessary . Growth factor pathway expression using epidermal growth factor receptor ( EGFR ) , mutant EGFR ( EGFRvIII ) , platelet derived growth factor receptor ( PDGFR ) , C-Kit and C-Abl together with phosphatase and tensin homolog ( PTEN ) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 ( P70S6K ) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors ( TKIs ) erlotinib , gefitinib and imatinib . Response to TKIs was assessed using 50% inhibitory concentrations ( IC(50) ) . Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis ( HCA ) and principal component analysis ( PCA ) . Erlotinib response was not strongly associated with high expression of the growth factor pathway components . PTEN expression did not correlate with response to any of the three TKIs . Increased EGFR expression was associated with gefitinib response ; increased PDGFR-α expression was associated with imatinib response . The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot183

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Epidermal growth factor ( EGF ) receptor is inversely related to expression of estrogen receptor ( ER ) and progesterone receptor in primary breast tumors and is a negative predictor for response to endocrine therapy . To investigate a possible causal role of EGF receptor expression in breast cancer progression to hormone independence , we have created an experimental cell system . Epidermal growth factor receptor complementary DNA was introduced in estrogen-dependent ZR-75-1 breast cancer cells , and the resulting ZR/HERc cells exhibited a mitogenic response to epidermal growth factor , thus bypassing estrogen dependence . This EGF-induced proliferation could not be inhibited by antiestrogens . In addition , we noted changes in cell morphology and keratin expression of EGF-stimulated ZR/HERc cells , suggestive of an altered differentiation state . Furthermore , intolerance of functional ER and EGF receptor signal transduction pathways in ZR/HERc cells was observed during simultaneous activation , which possibly explains the inverse relationship of ER and EGF receptor expression in primary tumors . In contrast to the parental cells , ZR/HERc cells rapidly progressed to a stable ER-negative phenotype when cultured in the presence of the antiestrogen hydroxy-tamoxifen . These results suggest a possible role for EGF receptor in progression of breast cancer to hormone independence . OUTPUT: sustaining proliferative signaling INPUT: Epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor 2 ( HER2 ) amplification occurs in over 30% of esophageal carcinomas . Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer . We evaluated the antitumor effects of lapatinib , a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2 , 5-fluorouracil ( 5-Fu ) alone and in combination on esophageal cancer cells . The antiproliferative activity of lapatinib , 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index ( CI ) values were calculated . Additionally , cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis . AnnexinV-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination . The EGFR and HER2 activated signaling pathways were monitored by western blotting . The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells . The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2 , and inhibited the activation of downstream signaling molecules , such as AKT and ERK . A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib , however , combination with 5-Fu did not enhance G1 arrest . These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot184

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Diphenyl ditelluride ( DPDT ) is a potential prototype for the development of novel biologically active molecules . Thus , it is important to evaluate the toxic effects of this compound . In the present study , we evaluated the cytotoxic , genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast ( V79 ) cells , in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium . DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae . Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT . The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells . At cytotoxic concentrations , this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells . DPDT generated single- and double-strand DNA breaks in V79 cells , both with and without metabolic activation , as revealed by alkaline and neutral comet assays . Moreover , an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III . Treatment with DPDT also induced micronucleus formation in V79 cells . Pre-incubation with N-acetylcysteine reduced DPDT's oxidative , genotoxic and mutagenic effects in yeast and V79 cells . Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell , which leads to oxidative stress and the induction of DNA damage . OUTPUT: genomic instability and mutation INPUT: D-Limonene , a common monoterepene has been shown to have antiproliferative , apoptosis-inducing and chemopreventive effects . In the present study , we have investigated the effects of D-limonene on the growth of 7,12-dimethylbenz[a]anthracene ( DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate ( TPA)-promoted skin tumor development . We found that D-limonene ( 50 and 100 mg/kg body weight ) treatments to the mouse skin significantly reduced the TPA-induced ( a ) edema and hyperplasia ( p &lt ; 0.001 ) ; ( b ) expression of cyclooxygenase-2 ; ( c ) ornithine decarboxylase activity ( p &lt ; 0.001 ) ; and ( d ) [ (3)H ] thymidine incorporation into DNA ( p &lt ; 0.001 ) . In addition , treatment of D-limonene effectively restored the level of reduced glutathione , glutathione peroxidase , glutathione reductase , glutathione S-transferase , catalase and malondialdehyde production in TPA-treated mouse skin . In a two-stage skin tumorigenesis study , D-limonene significantly reduced the tumor burden ( p &lt ; 0.005 ) and tumor incidence as compared to DMBA/TPA-treated mice . D-Limonene treatment also extended the latency period of tumor development from 4 to 9 weeks . D-Limonene treatment decreased the expression level of Ras , Raf and phosphorylation of extracellular signal-regulated protein kinase 1/2 in DMBA/TPA-induced tumors . A decrease in the expression of Bcl-2 and an increase in Bax expression were also observed in tumor tissues of mice treated with D-limonene . Taken together , our findings suggest that D-limonene may exert its chemopreventive activity through the inhibition of inflammation , oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state during TPA-mediated promotion of DMBA-induced skin cancer in mouse model . OUTPUT:

tumor promoting inflammation;resisting cell death

HoC_dynamic_1_shot185

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed . Meanwhile , methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors . Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable . This profile changes with microenvironmental conditions ( eg. substrate availability ) , the oncogenes activated ( and the tumor suppressors inactivated ) and the interaction with the stroma ( i.e. reverse Warburg effect ) . Here , we assessed the power of metabolic footprinting ( MFP ) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes , c-Myc , KLF4 and Oct1 . The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells . We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion . To investigate the potential oncogene-mediated alterations in mitochondrial metabolism , we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release . Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration . KLF4 deficiency also stimulated glycolysis , albeit without cellular respiration impairment . In contrast , Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency . MFP revealed that c-Myc , KLF4 and Oct1 altered amino acid metabolism with specific patterns . We identified isoleucine , α-aminoadipic acid and GABA ( γ-aminoisobutyric acid ) as biomarkers related . Our findings establish the impact of Oct1 , KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile . OUTPUT: cellular energetics INPUT: The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . A generally held notion is that the Warburg effect is related to energy . Using whole-genome , proteomic MALDI-TOF-MS and metabolite analysis , we investigated the Warburg effect in malignant neuroblastoma N2a cells . The findings show that the Warburg effect serves a functional role in regulating acidic pericellular pH ( pHe ) , which is mediated by metabolic inversion or a fluctuating dominance between glycolytic-rate substrate level phosphorylation ( SLP ) and mitochondrial ( mt ) oxidative phosphorylation ( OXPHOS ) to control lactic acid production . The results also show that an alkaline pHe caused an elevation in SLP/OXPHOS ratio ( approximately 98% SLP/OXPHOS ) ; while the ratio was approximately 56% at neutral pHe and approximately 93% in acidic pHe . Acidic pHe paralleled greater expression of mitochondrial biogenesis and OXPHOS genes , such as complex III-V ( Uqcr10 , Atp5 and Cox7c ) , mt Fmc1 , Romo1 , Tmem 173 , Tomm6 , aldehyde dehydrogenase , mt Sod2 mt biogenesis component PPAR-γ co-activator 1 adjunct to loss of mt fission ( Mff ) . Moreover , acidic pHe corresponded to metabolic efficiency evidenced by a rise in mTOR nutrient sensor GβL , its downstream target ( Eif4ebp1 ) , insulin modulators ( Trib3 and Fetub ) and loss of catabolic ( Hadhb , Bdh1 and Pygl)/glycolytic processes ( aldolase C , pyruvate kinase , Nampt and aldose-reductase ) . In contrast , alkaline pHe initiated loss of mitofusin 2 , complex II-IV ( Sdhaf1 , Uqcrq , Cox4i2 and Aldh1l2 ) , aconitase , mitochondrial carrier triple repeat 1 and mt biosynthetic ( Coq2 , Coq5 and Coq9 ) . In conclusion , the Warburg effect might serve as a negative feedback loop that regulates the pHe toward a broad acidic range by altering lactic acid production through inversion of metabolic systems . These effects were independent of changes in O(2) concentration or glucose supply . OUTPUT:

cellular energetics

HoC_dynamic_1_shot186

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Epidermal growth factor ( EGF ) receptor is inversely related to expression of estrogen receptor ( ER ) and progesterone receptor in primary breast tumors and is a negative predictor for response to endocrine therapy . To investigate a possible causal role of EGF receptor expression in breast cancer progression to hormone independence , we have created an experimental cell system . Epidermal growth factor receptor complementary DNA was introduced in estrogen-dependent ZR-75-1 breast cancer cells , and the resulting ZR/HERc cells exhibited a mitogenic response to epidermal growth factor , thus bypassing estrogen dependence . This EGF-induced proliferation could not be inhibited by antiestrogens . In addition , we noted changes in cell morphology and keratin expression of EGF-stimulated ZR/HERc cells , suggestive of an altered differentiation state . Furthermore , intolerance of functional ER and EGF receptor signal transduction pathways in ZR/HERc cells was observed during simultaneous activation , which possibly explains the inverse relationship of ER and EGF receptor expression in primary tumors . In contrast to the parental cells , ZR/HERc cells rapidly progressed to a stable ER-negative phenotype when cultured in the presence of the antiestrogen hydroxy-tamoxifen . These results suggest a possible role for EGF receptor in progression of breast cancer to hormone independence . OUTPUT: sustaining proliferative signaling INPUT: OBJECTIVES To investigate the immunoexpression of epidermal growth factor receptor ( EGFR ) in a sample of oral leukoplakias ( OL ) and to determine the receptor ' s association with dysplasia , tobacco consumption , lesion site , and proliferation rate . Although EGFR should be overexpressed in some oral leukoplakias , the factors that may interfere with this expression and the influence of this receptor on epithelial proliferation have yet to be investigated . STUDY DESIGN Samples of oral leukoplakias ( 48 ) and of normal oral epithelium ( 10 ) were immunohistologically examined for expression of EGFR . Immunohistochemistry for Ki-67 , and p27 were also performed in leukoplakias . EGFR expression was associated with clinical and pathological features . RESULTS EGFR was positive in 62.5% of the leukoplakias and 50% of normal oral epithelium . The number of EGFR positive OL located in high-risk sites was significantly higher than EGFR positive OL located in low-risk sites . Most of the p27 negative leukoplakias were EGFR positive , and the p27 index in the parabasal layer was diminished in the presence of dysplasia . Positivity for EGFR was not associated with dysplasia , tobacco exposure , or Ki-67 . CONCLUSION EGFR is expressed in leukoplakia regardless of dysplasia , but EGFR positivity should be more frequent in lesions sited in areas of high cancer risk . The association between EGFR and p27 may represent an important mechanism in the control of cellular proliferation and malignant progression of oral epithelium and therefore warrants further investigation . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot187

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Estrogen receptor α ( ERα ) expression in breast cancer is predictive of response to endocrine therapy ; however , resistance is common in ERα-positive tumors that overexpress the growth factor receptor ERBB2 . Even in the absence of estrogen , ERα can be activated by growth factors , including the epidermal growth factor ( EGF ) . EGF induces a transcriptional program distinct from estrogen ; however , the mechanism of the stimulus-specific response is unknown . Here we show that the EGF-induced ERα genomic targets , its cistromes , are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1 . The EGF-induced ERα cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers . This provides a potential molecular explanation for the endocrine therapy resistance seen in ERα-positive breast cancers that overexpress ERBB2 . These results suggest a central role for ERα in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERα , as opposed to blocking its estrogen responsiveness alone . OUTPUT: sustaining proliferative signaling INPUT: Whereas estrogen-estrogen receptor α ( ER ) signaling plays an important role in breast cancer growth , it is also necessary for the differentiation of normal breast epithelial cells . How this functional conversion occurs , however , remains unknown . Based on a genome-wide sequencing study that identified mutations in several breast cancer genes , we examined some of the genes for mutations , expression levels , and functional effects on cell proliferation and tumorigenesis . We present the data for C1orf64 or ER-related factor ( ERRF ) from 31 cell lines and 367 primary breast cancer tumors . Whereas mutation of ERRF was infrequent ( 1 of 79 or 1.3% ) , its expression was up-regulated in breast cancer , and the up-regulation was more common in lower-stage tumors . In addition , increased ERRF expression was significantly associated with ER and/or progesterone receptor ( PR ) positivity , which was still valid in human epidermal growth factor receptor 2 ( HER2)-negative tumors . In ER-positive tumors , ERRF expression was inversely correlated with HER2 status . Furthermore , higher ERRF protein expression was significantly associated with better disease-free survival and overall survival , particularly in ER- and/or PR-positive and HER2-negative tumors ( luminal A subtype ) . Functionally , knockdown of ERRF in two ER-positive breast cancer cell lines , T-47D and MDA-MB-361 , suppressed cell growth in vitro and tumorigenesis in xenograft models . These results suggest that ERRF plays a role in estrogen-ER-mediated growth of breast cancer cells and could , thus , be a potential therapeutic target . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot188

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Estrogen receptor α ( ERα ) expression in breast cancer is predictive of response to endocrine therapy ; however , resistance is common in ERα-positive tumors that overexpress the growth factor receptor ERBB2 . Even in the absence of estrogen , ERα can be activated by growth factors , including the epidermal growth factor ( EGF ) . EGF induces a transcriptional program distinct from estrogen ; however , the mechanism of the stimulus-specific response is unknown . Here we show that the EGF-induced ERα genomic targets , its cistromes , are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1 . The EGF-induced ERα cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers . This provides a potential molecular explanation for the endocrine therapy resistance seen in ERα-positive breast cancers that overexpress ERBB2 . These results suggest a central role for ERα in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERα , as opposed to blocking its estrogen responsiveness alone . OUTPUT: sustaining proliferative signaling INPUT: Estrogens play essential roles in the progression of mammary and prostatic diseases . The transcriptional effects of estrogens are transduced by two estrogen receptors , ERα and ERβ , which elicit opposing roles in regulating proliferation : ERα is proliferative while ERβ is anti-proliferative . Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo , suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers . Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors , the biological roles of the ERα/β heterodimer remain to be elucidated . Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based , two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity . Using ERα/β heterodimer-selective ligands at defined concentrations , we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms . Furthermore , using Automated Quantitative Analysis ( AQUA ) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays , we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors . The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions , further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot189

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Alterations of the epidermal growth factor receptor ( EGFR ) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7 . We have previously shown that this mutant receptor , called DeltaEGFR , confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo . To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation , we examined the gene products that control cell cycle progression . We found that levels of the cyclin-dependent kinase ( CDK ) inhibitor , p27 , were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors . Consequently , CDK2-cyclin A activity was also elevated , concomitant with the RB protein hyperphosphorylation . In addition , activated phosphatidylinositol 3-kinase ( PI3-K ) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors . U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB . Treatment of U87MG.DeltaEGFR cells with LY294002 , a PI3-K inhibitor , caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27 . Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo . These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway . This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: An acquired mutation ( T790M ) in the epidermal growth factor receptor ( EGFR ) accounts for half of all relapses in non-small cell lung cancer ( NSCLC ) patients who initially respond to EGFR kinase inhibitors . In this study , we demonstrated for the first time that EGFR-T790M interacts with the cytoskeletal components , myosin heavy chain 9 ( MYH9 ) and β-actin , in the nucleus of H1975 cells carrying the T790M-mutant EGFR . The interactions of EGFR with MYH9 and β-actin were reduced in the presence of blebbistatin , a specific inhibitor for the MYH9-β-actin interaction , suggesting that the EGFR interaction with MYH9 and β-actin is affected by the integrity of the cytoskeleton . These physical interactions among MYH9 , β-actin , and EGFR were also impaired by CL-387,785 , a kinase inhibitor for EGFR-T790M . Furthermore , CL-387,785 and blebbistatin interacted in a synergistic fashion to suppress cell proliferation and induce apoptosis in H1975 cells . The combination of CL-387,785 and blebbistatin enhanced the down-regulation of cyclooxygenase-2 ( COX-2 ) , a transcriptional target of nuclear EGFR . Overall , our findings demonstrate that disrupting EGFR interactions with the cytoskeletal components enhanced the anti-cancer effects of CL-387,785 against H1975 cells , suggesting a novel therapeutic approach for NSCLC cells that express the drug-resistant EGFR-T790M . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot190

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Both the deregulation of microRNAs and epidermal growth factor receptor ( EGFR ) are emerging as important factors in non-small-cell lung cancer ( NSCLC ) . Here , miR-133b was found to be associated with tumor stage , the extent of regional lymph node involvement , stage , visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC . Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3'-UTR of EGFR mRNA . Functionally , miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA . Moreover , miR-133b transfection may modulate apoptosis , invasion and sensitivity to EGFR-TKI through the EGFR signaling pathways , especially in EGFR-addicted NSCLC cells . Taken together , our findings show that miR-133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway . This finding has important implications for the development of targeted therapeutics for a number of EGFR-addicted cancers . OUTPUT: sustaining proliferative signaling;activating invasion and metastasis;resisting cell death INPUT: It has been shown that regulation of EGFR expression in prostate cancer cells is mostly at the transcriptional level. microRNA-133 ( miR-133 ) has long been recognized as a muscle-specific miRNA which may regulate myoblast differentiation and participate in many myogenic diseases . Recently , it has been reported that miR-133 is also involved in other tumors , such as bladder cancer , esophageal cancer and may regulate cell motility in these cancer cells . In the present study , we examined the expression and effects of miR-133 in two hormone-insensitive prostate cancer cell lines . The expression of miR-133a and miR-133b were analyzed by quantitative RT-PCR . After transfection of miR-133a and miR-133b , cell viability assay , luciferase assay , western blot analysis , cell migration and invasion assay were conducted in Du145 and PC3 cells . In this study , we showed that miR‑133a and miR-133b are expressed at the detection limit in two hormone-insensitive prostate cancer cell lines , PC3 and DU145 . Ectopic expression of miR-133 inhibited cell proliferation , migration and invasion in these cells . We also provide the first evidence that miR-133 may target EGFR . Our study provided the first glimpse of the functional role of miR-133 in two hormone-independent prostate cancer cell lines . These results may add to our knowledge on the molecular basis of prostate cancer progression . OUTPUT:

activating invasion and metastasis;sustaining proliferative signaling

HoC_dynamic_1_shot191

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Aims : RAS-induced tumorigenesis has been suggested to follow a three-stage model consisting of an initial RAS activation , senescence induction , and evasion of p53-dependent senescence checkpoints . While reactive oxygen species ( ROS ) act as second messengers in RAS-induced senescence , they are also involved in oncogenic transformation by inducing proliferation and promoting mutations . In the current work , we investigated the role of extracellular superoxide dismutase ( SOD3 ) in RAS-induced senescence and immortalization in vitro and in vivo . We used a mouse embryonic fibroblast ( MEF ) primary cell model together with immortalized and transformed human cell lines derived from papillary and anaplastic thyroid cancer . Results : Based on our data , sod3 RNA interference in H-RasV12-transduced cells markedly inhibited cell growth , while sod3 over-expression in MEFs initially caused a proliferative burst followed by the activation of DNA damage checkpoints , induction of p53-p21 signal transduction , and senescence . Subsequently , sod3-transduced MEF cells developed co-operative p21-p16 down-regulation and acquired transformed cell characteristics such as increased telomerase activity , loss of contact inhibition , growth in low-nutrient conditions , and in vivo tumorigenesis . Interestingly , as reported previously with RAS , we showed a dose-dependent response to SOD3 in vitro and in vivo involving transcriptional and non-transcriptional regulatory mechanisms . Innovation : SOD3 may mediate H-RasV12-induced initiation of primary cell immortalization . Conclusions : Our results indicate that SOD3 influences growth signaling in primary and cancer cells downstream of the ras oncogene and could serve as a therapy target at an early tumorigenesis phase . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;tumor promoting inflammation;sustaining proliferative signaling INPUT: Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 ( IL-3)-dependent murine cell lines like Ba/F3 , resulting in loss of IL-3 dependence . Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia ( AML ) cell lines , despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients . We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death , involving Bax/Bcl2 modulation . Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs , shown here using the HL-60 leukemic cell line . Flt3 expression was investigated in two cellular model systems , the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line , and proliferation was reduced in both systems . HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2 . Furthermore , we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent . Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot192

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The high glucose consumption of tumor cells even in an oxygen-rich environment , referred to as the Warburg effect , has been noted as a nearly universal biochemical characteristic of cancer cells . Targeting the glycolysis pathway has been explored as an anti-cancer therapeutic strategy to eradicate cancer based on this fundamental biochemical property of cancer cells . Oncoproteins such as Akt and c-Myc regulate cell metabolism . Accumulating studies have uncovered various molecular mechanisms by which oncoproteins affect cellular metabolism , raising a concern as to whether targeting glycolysis will be equally effective in treating cancers arising from different oncogenic activities . Here , we established a dual-regulatable FL5.12 pre-B cell line in which myristoylated Akt is expressed under the control of doxycycline , and c-Myc , fused to the hormone-binding domain of the human estrogen receptor , is activated by 4-hydroxytamoxifen . Using this system , we directly compared the effect of these oncoproteins on cell metabolism in an isogenic background . Activation of either Akt or c-Myc leads to the Warburg effect as indicated by increased cellular glucose uptake , glycolysis , and lactate generation . When cells are treated with glycolysis inhibitors , Akt sensitizes cells to apoptosis , whereas c-Myc does not . In contrast , c-Myc but not Akt sensitizes cells to the inhibition of mitochondrial function . This is correlated with enhanced mitochondrial activities in c-Myc cells . Hence , although both Akt and c-Myc promote aerobic glycolysis , they differentially affect mitochondrial functions and render cells susceptible to the perturbation of cellular metabolic programs . OUTPUT: cellular energetics INPUT: Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis or the Warburg effect , and the cells resist matrix detachment-induced apoptosis , which is called anoikis , a barrier to metastasis . It remains largely unclear whether tumor metabolism influences anoikis and metastasis . Here we show that when detached from the matrix , untransformed mammary epithelial cells undergo metabolic reprogramming by markedly upregulating pyruvate dehydrogenase ( PDH ) kinase 4 ( PDK4 ) through estrogen-related receptor gamma ( ERRγ ) , thereby inhibiting PDH and attenuating the flux of glycolytic carbon into mitochondrial oxidation . To decipher the significance of this metabolic response , we found that depletion of PDK4 or activation of PDH increased mitochondrial respiration and oxidative stress in suspended cells , resulting in heightened anoikis . Conversely , overexpression of PDKs prolonged survival of cells in suspension . Therefore , decreased glucose oxidation following cell detachment confers anoikis resistance . Unlike untransformed cells , most cancer cells demonstrate reduced glucose oxidation even under attached conditions , and thus they inherently possess a survival advantage when suspended . Normalization of glucose metabolism by stimulating PDH in cancer cells restores their susceptibility to anoikis and impairs their metastatic potential . These results suggest that the Warburg effect , more specifically , diminished glucose oxidation , promotes anoikis resistance and metastasis and that PDKs are potential targets for antimetastasis therapy . OUTPUT:

cellular energetics;sustaining proliferative signaling;activating invasion and metastasis

HoC_dynamic_1_shot193

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC₅₀ value of 5 μg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 μg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation . OUTPUT: evading growth suppressors;resisting cell death INPUT: OBJECTIVE To investigate the effects of CdTe QDs ( cadmium telluride quantum dots ) on oxidative stress and DNA damage of liver cells in mice . METHODS Thirty ICR male mice were randomly divided into 5 groups : one negative control ( normal saline ) group . Three CdTe QDs groups ( exposed by intravenous injection of 0.2 ml of CdTe QDs at the concentration of 3.75 , 37.5 and 375 nmol/ml respectively ) for electron paramagnetic resonance ( EPR ) test , and another positive control group ( exposed by intravenous injection of 0.2 ml of cyclophosphamide 20 mg/ml ) for single cell gel electrophoresis ( SCGE ) test . All mice were decapitated 24h after the injection , free radicals and DNA damage of liver cells were detected by EPR and SCGE . RESULTS The levels of oxygen free radicals detected by EPR were increased with the increase of CdTe QDs . The tail length , olive tail moment , tail DNA ( % ) and the ratio of tail/head examined by SCGE were also increased with the increase of the dosage of CdTe QDs ( P &lt ; 0.01 ) . CONCLUSION CdTe QDs could induce oxidative stress and DNA damage of liver cells in mice with a dose-effect relationship . OUTPUT:

tumor promoting inflammation;genomic instability and mutation

HoC_dynamic_1_shot194

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Ulcerative colitis ( UC ) is a major form of chronic inflammation that can frequently progress to colon cancer . Several studies have demonstrated massive infiltration of neutrophils and macrophages into the lamina propria and submucosa in the progression of UC-associated colon carcinogenesis . Macrophages contribute to the development of colitis-associated colon cancer ( CAC ) . However , the role of neutrophils is not well understood . To better understand the involvement of tumor-associated neutrophils ( TANs ) in the regulation of CAC , we used a mouse CAC model produced by administering azoxymethane ( AOM ) , followed by repeated dextran sulfate sodium ( DSS ) ingestion . This causes severe colonic inflammation and subsequent development of multiple tumors in mice colon . We observed that colorectal mucosal inflammation became increasingly severe with AOM and DSS treatment . Macrophages infiltrated the lamina propria and submucosa , together with a marked increase in neutrophil infiltration . The chemokine CXCL2 increased in the lamina propria and submucosal regions of the colons of the treated mice , together with the infiltration of neutrophils expressing CXCR2 , a specific receptor for CXCL2 . This process was followed by neoplastic transformation . After AOM and DSS treatment , the mice showed enhanced production of metalloproteinase ( MMP)-9 and neutrophil elastase ( NE ) , accompanied by excessive vessel generation and cell proliferation . Moreover , CXCL2 promoted neutrophil recruitment and induced neutrophils to express MMP-9 and NE in vitro . Furthermore , administration of neutrophil-neutralizing antibodies after the last DSS cycle markedly reduced the number and size of tumors and decreased the expression of CXCR2 , CXCL2 , MMP-9 , and NE . These observations indicate a crucial role for TANs in the initiation and progression of CAC and suggest that the CXCL2-CXCR2 axis might be useful in reducing the risk of UC-associated colon cancer . OUTPUT: tumor promoting inflammation;inducing angiogenesis INPUT: Carboxypeptidase M ( CPM ) targets the basic amino acids arginine and lysine present at the C-terminus of peptides or proteins . CPM is thought to be involved in inflammatory processes . This is corroborated by CPM-mediated trimming and modulation of inflammatory factors , and expression of the protease in inflammatory environments . Since the function of CPM in and beyond inflammation remains mainly undefined , the identification of natural substrates can aid in discovering the ( patho)physiological role of CPM . CCL1/I-309 , with its three C-terminal basic amino acids , forms a potential natural substrate for CPM . CCL1 plays a role not only in inflammation but also in apoptosis , angiogenesis and tumor biology . Enzymatic processing differently impacts the biological activity of chemokines thereby contributing to the complex regulation of the chemokine system . The aim of the present study was to investigate whether ( i ) CCL1/I-309 is prone to trimming by CPM , and ( ii ) the biological activity of CCL1 is altered after C-terminal proteolytic processing . CCL1 was identified as a novel substrate for CPM in vitro using mass spectrometry . C-terminal clipping of CCL1 augmented intracellular calcium release mediated by CCR8 but reduced the binding of CCL1 to CCR8 . In line with the higher intracellular calcium release , a pronounced increase of the anti-apoptotic activity of CCL1 was observed in the BW5147 cellular model . CCR8 signaling , CCR8 binding and anti-apoptotic activity were unaffected when CPM was exposed to the carboxypeptidase inhibitor DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid . The results of this study suggest that CPM is a likely candidate for the regulation of biological processes relying on the CCL1-CCR8 system . OUTPUT:

resisting cell death

HoC_dynamic_1_shot195

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: OBJECTIVE To study the effects of genistein on the proliferation , apoptosis induction and expression of related gene proteins of human colon cancer cells in vitro and in vivo , and its mechanisms of action . METHODS MTT colorimetric assay was used to detect the effects of genistein on the proliferation of human colon adenocarcinoma SW480 cells . Light and transmission electron microscopy were used to study the histological and ultrastructural changes . Flow cytometry was used to determine the effects of genistein on cell cycle and apoptosis . Flow cytometry and immunohistochemistry were used to determine the effects of genistein on apoptosis induction and expression of related gene proteins of colon cancer cells . RESULTS The MTT colorimetric assay showed that genistein inhibited the proliferation of SW480 cells in a dose-dependent and time-dependent manner , and the highest inhibition rate was 60.2% after 80 microg/ml genistein treatment for 72 h . The light microscopy revealed that many genistein-treated cancer cells were shrunken , disrupted , or showing cytoplasmic vacuolization . The electron microscopic examination showed cell shrinkage , nuclear fragmentation and pronounced chromatin condensation , sometimes formed crescent chromatin condensation attached to the nuclear membrane . The results of flow cytometry showed that : after SW480 cells were treated with 0 , 20 , 40 , 80 microg/ml genistein for 48 h , the FI values of PCNA were 1.49 +/- 0.02 , 1.28 +/- 0.04 , 1.14 +/- 0.03 , and 0.93 +/- 0.08 ; the FI values of VEGF were 1.75 +/- 0.02 , 1.34 +/- 0.06 , 1.32 +/- 0.04 , and 1.23 +/- 0.04 ; the fluorescence index ( FI ) values of p21 were 1.26 +/- 0.05 , 1.36 +/- 0.06 , 1.61 +/- 0.03 , and 1.73 +/- 0.03 , respectively . There were statistically significant differences between the control group and each treatment group ( P &lt ; 0.05 or P &lt ; 0.01 ) . The scores of immunohistochemical staining of PCNA and VEGF proteins were decreased , while p21 increased . There were statistically significant differences between the control group and each treatment group ( P &lt ; 0.05 or P &lt ; 0.01 ) . CONCLUSION Genistein can inhibit the growth of colon cancer cells via apoptosis induction and cell cycle arrest at G(2)/M phase . The anti-tumor mechanisms of genistein may be related with the down-regulation of expression of VEGF and PCNA , and up-regulation of the expression of p21 . OUTPUT: resisting cell death;evading growth suppressors;sustaining proliferative signaling;inducing angiogenesis INPUT: AIM We studied expression of molecules of the vascular endothelial growth factor ( VEGF ) pathway and its relation to vascularization , cell proliferation and patient outcome in recurring non-anaplastic meningioma . We studied 29 tumor specimens of 8 patients with recurring meningiomas and of 8 age- and gender-matched control patients with non-recurring meningiomas ( including meningothelial , transitional , fibroblastic and atypical subtypes ) using immunohistochemistry and in-situ hybridization . RESULTS VEGF protein , VEGF-mRNA , VEGF receptor ( VEGFR)-1 mRNA , VEGFR-2 mRNA and hypoxia-inducible factor ( HIF)-1-α protein were expressed in 27/29 ( 93% ) , 20/27 ( 74% ) , 9/27 ( 33.3% ) , 12/27 ( 44.4% ) and 5/29 ( 17.2% ) specimens , respectively . VEGFR- 2 mRNA expression was found in 6/8 tumors extracted at first operation in patients with recurring tumors and in none of the control cases ( p = 0.007 ) . Microvessel density ( MVD ) and Ki-67 index values were generally higher in meningiomas with expression of angiogenic factors . The association of high Ki-67 index values with VEGF-mRNA expression was significant ( p = 0.04 ) . Time to recurrence was shorter in patients with high MVD than in patients with low MVD ( p = 0.027 ) . CONCLUSIONS High MVD correlates with unfavorable prognosis in our series of recurring meningioma . VEGF and its receptors are frequently expressed in meningiomas and seem important for tumor growth and recurrence . Thus , anti-VEGF therapy in aggressive meningioma seems rational from a pathobiological point of view . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot196

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: The phosphatidylinositol-3-kinase ( PI3K)/Akt oncogenic pathway is critical in glioblastomas . Loss of PTEN , a negative regulator of the PI3K pathway or activated PI3K/Akt pathway that drive increased proliferation , survival , neovascularization , glycolysis , and invasion is found in 70%-80% of malignant gliomas . Thus , PI3K is an attractive therapeutic target for malignant glioma . We report that a new irreversible PI3K inhibitor , PX-866 , shows potent inhibitory effects on the PI3K/Akt signaling pathway in glioblastoma . PX-866 did not induce any apoptosis in glioma cells ; however , an increase in autophagy was observed . PX-866 inhibited the invasive and angiogenic capabilities of cultured glioblastoma cells . In vivo , PX-866 inhibited subcutaneous tumor growth and increased the median survival time of animals with intracranial tumors . We also assessed the potential of proton magnetic resonance spectroscopy ( MRS ) as a noninvasive method to monitor response to PX-866 . Our findings show that PX-866 treatment causes a drop in the MRS-detectable choline-to-NAA , ratio and identify this partial normalization of the tumor metabolic profile as a biomarker of molecular drug action . Our studies affirm that the PI3K pathway is a highly specific molecular target for therapies for glioblastoma and other cancers with aberrant PI3K/PTEN expression . OUTPUT: sustaining proliferative signaling;resisting cell death INPUT: The phosphoinositide 3-kinase ( PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers . In many cases , concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage . Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway , thereby decreasing the effectiveness of single-agent targeted therapies . In this study , we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers . We found that MEK inhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2 . Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway , which was no longer responsive to MEK inhibition . Taken together , these results elucidate an important , dominant feedback network regulating central oncogenic pathways in human cancer . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot197

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells . Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines . Since new compounds with biological activity are needed , the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones , derived from 1-naphthaldehyde and 2-naphthaldehyde , on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells . Based on the results , the most cytotoxic compound ( A1 ) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line ( HT-29 ) . Chalcone A1 significantly reduced the cell viability of K562 , Jurkat , Kasumi , U937 , CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group ( IC(50) values between ∼1.5μM and 40μM ) . It was also cytotoxic to HL-29 cells . To further examine its effect on normal cells , peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound . It has also been incubated with human fibroblasts cultured from bone marrow ( JMA ) . Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells . A1 caused significant cell cycle arrest in all phases according to the cell line , and increased the proportion of cells in the sub G0/G1 phase . To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway , cell morphology was examined using fluorescence microscopy . Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis , such as chromatin condensation and formation of apoptotic bodies . Apoptosis was confirmed by externalization of phosphatidylserine , which was detected by the Annexin V-FITC method , and by DNA fragmentation . The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: BACKGROUND Apigenin , a natural plant flavone , may have chemopreventive and therapeutic potentials for anti-inflammatory , antioxidant , and anti-cancer . Nevertheless , the anti-tumor effect of apigenin on human head and neck squamous cell carcinoma ( HNSCC ) is not fully understood . METHODS The antioxidant capacity and protective effects of apigenin against oxidative stress in murine normal embryonic liver BNLCL2 cells are examined . Cell viability , morphologic change , clonogenic survival , cell cycle distribution , reactive oxygen species ( ROS ) production , glutathione formation , and death receptors- and Bcl-2-mediated caspase pathways of HNSCC SCC25 cells and A431 cells with apigenin are investigated . RESULTS Apigenin inhibits the growth of SCC25 and A431 cells and induces cell cycle arrest in the G2/M phase . Apigenin has an antioxidant capacity as well as the ability to inhibit lipid peroxidation . It protects BNLCL2 cells against oxidative damage , and is potentially able to prevent cancer . Apigenin increases intracellular ROS levels and reduces levels of glutathione ; it also induces cell apoptosis via tumor necrosis factor receptor ( TNF-R)- , TNF-related apoptosis-inducing ligand receptor ( TRAIL-R)- , and Bcl-2-mediated caspase-dependent cell death pathways in SCC25 cells . The combination of apigenin with 5-fluorouracil ( 5-Fu ) or cisplatin induces the dramatic death of SCC25 cells . CONCLUSIONS Apigenin induces SCC25 cell apoptosis via the up-regulation of both TNF-R and TRAIL-R signaling pathways , and has a synergistic effect on the inhibition of cell proliferation in combination with 5-Fu or cisplatin . GENERAL SIGNIFICANCE These analytical findings suggest that apigenin may be a good therapeutic agent against HNSCC cells . OUTPUT:

sustaining proliferative signaling;tumor promoting inflammation;genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot198

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND The current staging system provides an anatomical classification of lung tumors ; its secondary purpose is to allow the prognostic stratification of patients into homogeneous groups after surgery . In this work , intratumoral perineural invasion , lymphatic and blood vessel invasion together with the necrosis content of the tumor exclusive of the non-small cell cancer staging system were studied . METHODS During a 4-year period , 152 patients operated for non-small cell lung cancer ( NSCLC ) at our hospital were analyzed . Mean age of patients was 55.7 +/- 10.1 years . RESULTS Overall 5-year survival was 42.2 % . Mediastinal lymph node involvement , tumor size , incomplete resection , pneumonectomy , presence of necrosis and perineural invasion were significant prognosticators ( P = 0.03 , 0.04 , 0.0001 , 0.046 , 0.0246 , &lt ; 0.0001 , respectively ) . Multivariate analysis revealed that N status , perineural invasion , and the presence of necrosis were independent prognostic factors ( P = 0.006 , P = 0.001 , P = 0.001 , respectively ) . Patients who had stage I tumor with necrosis and perineural invasion had a lower survival rate than those with stage IIIA tumor without these histopathological features ( P = 0.04 ) . The presence of these histopathological characteristics in stage IIIA patients was a sign of a poorer prognosis ( P = 0.0001 ) . CONCLUSIONS Perineural invasion and the presence of necrosis independently indicated a dismal prognosis and their prognostic power is comparable to those of the TNM classification . These factors could be candidates for better survival stratification and the indicators of the need for adjuvant therapy in early stage lung cancer patients . OUTPUT: activating invasion and metastasis;resisting cell death INPUT: Surgery is the most effective therapy for cancer in the United States , but disease still recurs in more than 40% of patients within 5 years after resection . Chemotherapy is given postoperatively to prevent relapses ; however , this approach has had marginal success . After surgery , recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen . Phosphatidylserine ( PS ) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues . Thus , PS is an attractive target for cancer therapy after surgery . Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 ( a novel mouse chimeric monoclonal antibody that targets PS ) , cisplatin ( cis ) , or combination after surgery . Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone ( P = .02 ) . Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals . Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells , particularly granulocytes . This strategy was independent of the adaptive immune system . Together , these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery . OUTPUT:

tumor promoting inflammation;inducing angiogenesis

HoC_dynamic_1_shot199

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: "We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism . In this model , glycolytic stromal cells produce mitochondrial fuels ( L-lactate and ketone bodies ) that are then transferred to oxidative epithelial cancer cells , driving OXPHOS and mitochondrial metabolism . Thus , stromal catabolism fuels anabolic tumor growth via energy transfer . We have termed this new cancer paradigm the "" reverse Warburg effect, "" because stromal cells undergo aerobic glycolysis , rather than tumor cells . To assess whether this mechanism also applies during cancer cell metastasis , we analyzed the bioenergetic status of breast cancer lymph node metastases , by employing a series of metabolic protein markers . For this purpose , we used MCT4 to identify glycolytic cells . Similarly , we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity , respectively . Consistent with the "" reverse Warburg effect, "" our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism ( OXPHOS ) and that adjacent stromal cells are glycolytic and lack detectable mitochondria . Glycolytic stromal cells included cancer-associated fibroblasts , adipocytes and inflammatory cells . Double labeling experiments with glycolytic ( MCT4 ) and oxidative ( TO MM20 or COX ) markers directly shows that at least two different metabolic compartments co-exist , side-by-side , within primary tumors and their metastases . Since cancer-associated immune cells appeared glycolytic , this observation may also explain how inflammation literally "" fuels "" tumor progression and metastatic dissemination , by "" feeding "" mitochondrial metabolism in cancer cells . Finally , MCT4(+) and TO MM20(-) "" glycolytic "" cancer cells were rarely observed , indicating that the conventional "" Warburg effect "" does not frequently occur in cancer-positive lymph node metastases ." OUTPUT: activating invasion and metastasis;cellular energetics;tumor promoting inflammation INPUT: "High glycolysis , well known as "" Warburg effect, "" is frequently observed in a variety of cancers . Whether the deregulation of miRNAs contributes to the Warburg effect remains largely unknown . Because miRNA regulates gene expression at both mRNA and protein levels , we constructed a gene functional association network , which allows us to detect the gene activity instead of gene expression , to integratively analyze the microarray data for gene expression and miRNA expression profiling and identify glycolysis-related gene-miRNA pairs deregulated in cancer . Hexokinase 2 ( HK2 ) , coding for the first rate-limiting enzyme of glycolysis , is among the top list of genes predicted and potentially regulated by multiple miRNAs including miR-143 . Interestingly , miR-143 expression was inversely associated with HK2 protein level but not mRNA level in human lung cancer samples. miR-143 , down-regulated by mammalian target of rapamycin activation , reduces glucose metabolism and inhibits cancer cell proliferation and tumor formation through targeting HK2 . Collectively , we have not only established a novel methodology for gene-miRNA pair prediction but also identified miR-143 as an essential regulator of cancer glycolysis via targeting HK2 ." OUTPUT:

cellular energetics