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HoC_dynamic_1_shot_test

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HoC_dynamic_1_shot200

***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: It is prevailingly thought that the antiestrogens tamoxifen and ICI 182 , 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha ( ER-α ) . However , a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways . The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established . Previously , a variant of ER-α , EP-α36 , has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-α36 . Here , we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of endogenous ER-α36 . We found that the effects of both 4-hydoxytamoxifen ( 4-OHT ) and ICI 182 , 780 ( ICI ) exhibited a non-monotonic , or biphasic dose response curve ; antiestrogens at low concentrations , elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations , antiestrogens inhibited cell growth . Antiestrogens at l nM induced the phosphorylation of the Src-Y416 residue , an event to activate Src , while at 5 �M induced Src-Y527 phosphorylation that inactivates Src . Antiestrogens at 1 nM also induced phosphorylation of the MAPK/ERK and activated the Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at 5 �M . Knock-down of ER-α36 abrogated the biphasic antiestrogen signaling in these cells . Our results thus indicated that ER-α36 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the EGFR/STAT5 pathway . OUTPUT: sustaining proliferative signaling INPUT: The effects of 17beta-estradiol ( E2 ) are mediated through activation of estrogen receptors ( ER ) : ERalpha and ERbeta . It is known that ERalpha/ERbeta ratio is higher in breast tumors than in normal tissue . Since antioxidant enzymes and uncoupling proteins ( UCPs ) are reactive oxygen species ( ROS ) production and mitochondrial biogenesis regulators , our aim was to study the E2-effect on oxidative stress , antioxidant enzyme expression , and UCPs in breast cancer cell lines with different ERalpha/ERbeta ratios . The lower ERalpha/ERbeta ratio T47D cell line showed low ROS production and high UCP5 levels . However , the higher ERalpha/ERbeta ratio MCF-7 cell line showed an up-regulation of antioxidant enzymes and UCPs , yet exhibited high oxidative stress . As a result , a decrease in antioxidant enzyme activities and UCP2 protein levels , coupled with an increase in oxidative damage was found . On the whole , these results show different E2-effects on oxidative stress regulation , modulating UCPs , and antioxidant enzymes , which were ERalpha/ERbeta ratio dependent in breast cancer cell lines . OUTPUT:

sustaining proliferative signaling;tumor promoting inflammation;genomic instability and mutation

HoC_dynamic_1_shot201

***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: Targeting receptor tyrosine kinase ( RTK ) degradation may be an interesting approach to reduce RTK cell signaling in cancer cells . Here we show that increasing E3 ubiquitin ligase casitas B-lineage lymphoma ( c-Cbl ) expression using lentiviral infection decreased osteosarcoma cell replication and survival and reduced cell migration and invasion in murine and human osteosarcoma cells . Conversely , c-Cbl inhibition using short hairpin RNA ( shRNA ) increased osteosarcoma cell growth and survival , as well as invasion and migration , indicating that c-Cbl plays a critical role as a bone tumor suppressor . Importantly , the anticancer effect of increasing c-Cbl expression in osteosarcoma cells was related mainly to the downregulation of epidermal growth factor receptor ( EGFR ) and platelet-derived growth factor receptor alpha ( PDGFRα ) . In a murine bone tumor model , increasing c-Cbl expression also reduced RTK expression , resulting in decreased tumor cell proliferation and survival and reduced tumor growth . Interestingly , increasing c-Cbl also markedly reduced lung metastasis in mice . Tissue microarray analysis revealed that low c-Cbl protein expression is associated with elevated EGFR and PDGFRα protein levels in human osteosarcoma with poor outcome . This study shows that increasing c-Cbl expression reduces osteosarcoma cell growth , survival , and metastasis in part through downregulation of RTKs , which supports the potential therapeutic interest of targeting c-Cbl in malignant bone diseases involving increased RTK . OUTPUT:

activating invasion and metastasis;sustaining proliferative signaling

HoC_dynamic_1_shot202

***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: Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia ( ALL ) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse , supporting the need to use alternative therapies . CRLF2 encodes the thymic stromal lymphopoietin ( TSLP ) receptor , which activates cell signaling in normal lymphocytes on binding its ligand , TSLP . We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway . In a large number of primary CRLF2-rearranged ALL samples , we observed increased basal levels of pJAK2 , pSTAT5 , and pS6 . We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction . TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling . JAK inhibition abrogated phosphorylation of JAK/STAT and , surprisingly , of PI3K/mTOR pathway members , suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials . The PI3K/mTOR pathway inhibitors rapamycin , PI103 , and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway , suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot203

***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 analyze the profiles of interleukin-2 ( IL-2 ) , IL-6 , IL-8 , IL-10 , tumor necrosis factor-alpha ( TNF-alpha ) , transforming growth factor-beta1 ( TGF-beta1 ) and interferon-gamma ( IFN-gamma ) in serum and the tumor microenvironment ( cyst fluid , ascites ) in women with ovarian cancer or benign ovarian tumors to find the differences in their immunological status . We also estimated serum cytokines as biomarkers to distinguish preoperatively between malignant or benign character of tumors . DESIGN Prospective study . SETTING Tertiary referral hospital . POPULATION 51 women with epithelial ovarian cancer , 26 with benign ovarian tumors of epithelial origin and 21 healthy controls . METHODS The levels of cytokines were measured using ELISA sets . RESULTS We did not found differences in the levels of IFN-gamma , TNF-alpha and IL-2 in all fluids isolated from patients with malignant or benign tumors . Women with advanced cancer had significantly higher serum IL-6 , IL-10 and TGF-beta1 levels than women with early stages or benign tumors . Moreover , women with very advanced cancer in whom the optimal cytoreduction was disabled had the highest serum levels of IL-10 , TGF-beta1 and IL-8 . The concentrations of IL-6 and IL-8 were higher in ascites of cancer patients than in ascites of women with benign tumors . The areas under curves constructed for the selected cutoff serum cytokines levels ( AUC-ROC ) showed good predictive values for IL-6 ( 0.87 ) , IL-10 ( 0.836 ) and IL-8 ( 0.797 ) . CONCLUSIONS Our results indicate on intensified inflammatory process in women with ovarian cancer ( accompanied by their immunosuppression ) . Preoperative analysis of serum IL-6 , IL-10 and IL-8 may improve the differential diagnosis of ovarian tumors . OUTPUT: avoiding immune destruction;tumor promoting inflammation INPUT: OBJECTIVE Hepatocellular carcinoma ( HCC ) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis . We assessed the safety , efficacy , and potential biomarkers of activity of bevacizumab in patients with advanced HCC . METHODS In this phase II trial , eligible patients received bevacizumab , 5 mg/kg or 10 mg/kg every 2 weeks . The disease-control rate at 16 weeks ( 16W-DCR ) was the primary endpoint . Circulating endothelial cells ( CECs ) and plasma cytokines and angiogenic factors ( CAFs ) were measured at baseline and throughout treatment . RESULTS The 16W-DCR was 42% ( 95% confidence interval , 27%-57% ) . Six of the 43 patients who received bevacizumab achieved a partial response ( objective response rate [ ORR ] , 14% ) . Grade 3-4 asthenia , hemorrhage , and aminotransferase elevation occurred in five ( 12% ) , three ( 7% ) , and three ( 7% ) patients , respectively . During treatment , placental growth factor markedly increased , whereas vascular endothelial growth factor ( VEGF)-A dramatically decreased ( p &lt ; .0001 ) ; soluble VEGF receptor-2 ( p &lt ; .0001 ) and CECs ( p = .03 ) transiently increased on day 3 . High and increased CEC counts at day 15 were associated with the ORR ( p = .04 ) and the 16W-DCR ( p = .02 ) , respectively . Lower interleukin ( IL)-8 levels at baseline ( p = .01 ) and throughout treatment ( p ≤ .04 ) were associated with the 16W-DCR . High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times ( p ≤ .04 ) . CONCLUSION Bevacizumab is active and well tolerated in patients with advanced HCC . The clinical value of CECs , IL-6 , and IL-8 warrants further investigation . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot204

***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: Induced pluripotent stem ( iPS ) cells share some basic properties , such as self-renewal and pluripotency , with cancer cells , and they also appear to share several metabolic alterations that are commonly observed in human tumors . The cancer cells ' glycolytic phenotype , first reported by Otto Warburg , is necessary for the optimal routing of somatic cells to pluripotency . However , how iPS cells establish a Warburg-like metabolic phenotype and whether the metabolic pathways that support the bioenergetics of iPS cells are produced by the same mechanisms that are selected during the tumorigenic process remain largely unexplored . We recently investigated whether the reprogramming-competent metabotype of iPS cells involves changes in the activation/expression status of the H ( + ) -ATPase , which is a core component of mitochondrial oxidative phosphorylation that is repressed at both the activity and protein levels in human carcinomas , and of the lipogenic switch , which refers to a marked overexpression and hyperactivity of the acetyl-CoA carboxylase ( ACACA ) and fatty acid synthase ( FASN ) lipogenic enzymes that has been observed in nearly all examined cancer types . A comparison of a starting population of mouse embryonic fibroblasts and their iPS cell progeny revealed that somatic cell reprogramming involves a significant increase in the expression of ATPase inhibitor factor 1 ( IF1 ) , accompanied by extremely low expression levels of the catalytic β-F1-ATPase subunit . The pharmacological inhibition of ACACA and FASN activities markedly decreases reprogramming efficiency , and ACACA and FASN expression are notably upregulated in iPS cells . Importantly , iPS cells exhibited a significant intracellular accumulation of neutral lipid bodies ; however , these bodies may be a reflection of intense lysosomal/autophagocytic activity rather than bona fide lipid droplet formation in iPS cells , as they were largely unresponsive to pharmacological modulation of PPARgamma and FASN activities . The AMPK agonist metformin , which endows somatic cells with a bioenergetic infrastructure that is protected against reprogramming , was found to drastically elongate fibroblast mitochondria , fully reverse the high IF1/β-F1-ATPase ratio and downregulate the ACACA/FASN lipogenic enzymes in iPS cells . The mitochondrial H ( + ) -ATP synthase and the ACACA/FASN-driven lipogenic switch are newly characterized as instrumental metabolic events that , by coupling the Warburg effect to anabolic metabolism , enable de-differentiation during the reprogramming of somatic cells to iPS cells . OUTPUT: cellular energetics INPUT: The apoptotic effects of interferon lambdas ( IFNλs ) have been described in several types of cancers . However , their effects on human lung cancer cells and the mechanisms are elusive . In addition , the interaction between IFNλs and other interferons remains unclear . The interplay between IFNα and IFNλ has been reported . However , although IFNγ is a well-known regulatory interferon , the mechanisms through which it regulates IFNλs in lung cancer cells are unknown . These issues are critical for the application of IFNλs in lung cancer therapy . In this study , we used A549 , a cell line derived from a human lung carcinoma , to characterize the antiproliferative and apoptotic effects of IFNλs on lung cancer , and the interplay between IFNγ and IFNλ . Because overexpression of full-length ectopic IFNλR1 led to cell death , we generated A549 cells stably expressing a chimeric receptor ( 10R1/λR1 ) , which is composed of the extracellular domain of IL-10 receptor ( IL10R1 ) fused in tandem to the transmembrane and intracellular domains of the IFNλ receptor ( IFNλR1 ) . By comparing with A549 cells stably expressing its cognate vector , we demonstrated that IL-10 stimulation triggered the intracellular IFNλ signaling via 10R1/λR1 receptor . By using A549 cells expressing 10R1/λR1 , we report that the IFNλR1 chain of IFNλ receptor possesses an intrinsic ability to trigger apoptosis in human lung cancer cells . Although it did not suppress cell proliferation , IFNλ signaling via 10R1/λR1 receptor induced cell cycle arrest , externalization of phosphatidylserine , DNA fragmentation , activation of caspase-3 , caspase-8 and caspase-9 . However , the caspase inhibitor Z-VAD-FMK did not prevent apoptosis . In addition , the extent of induced apoptosis correlate with the expression levels of the IFNλ receptor and the levels of STAT1 activation . Lastly , we demonstrated that IFNγ sensitized A549 cells to IFNλ-induced apoptosis , via upregulation of IFNλR1 . These data indicate the potential of IFNλ , alone or in combination with IFNγ , in the treatment of human lung carcinoma . OUTPUT:

resisting cell death

HoC_dynamic_1_shot205

***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: Vascular endothelial growth factor A ( VEGF-A ) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis . SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase . We have developed a reproducible murine model for neuroblastoma , a childhood cancer , based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells . We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels , that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume &gt ; 1.4 ml , and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals . Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity . SU5416 treatment also suppressed tumor angiogenesis , despite an increase in plasma VEGF-A levels per ml tumor volume during therapy . Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma . OUTPUT: inducing angiogenesis INPUT: Vascular endothelial growth factor ( VEGF ) is one of the most important mediators of angiogenesis . Single-chain ( sc)-VEGF protein containing an N-terminal Cys-tag has been designed for site-specific modification with a variety of imaging and therapeutic moieties . Site-specific labeling of scVEGF with thiol-reactive prosthetic group , N-[2-(4-(18)F-fluorobenzamido) ethyl ] maleimide ( [ (18)F]FBEM ) for positron emission tomography ( PET ) imaging of VEFGR may provide a new tracer which has great potential for clinical translation.Methods : [ (18)F]FBEM-scVEGF was synthesized by site-specific conjugation of ( 18)F-FBEM to a thiol group in Cys-tag of scVEGF at room temperature . The functional activity after labeling was tested by immunofluorescence staining , cellular uptake and efflux . The tumor targeting and in vivo properties were evaluated by biodistribution and microPET studies in tumor-bearing mice.Results : The radiolabeling yield and specific activity of [ (18)F]FBEM-scVEGF were 20.6 � 15.1% ( based on starting [ (18)F]FBEM , uncorrected , n = 5 ) and 58.8 � 12.4 GBq/�mol , respectively . Noninvasive microPET and direct tissue sampling experiments demonstrated that [ (18)F]FBEM-scVEGF had VEGFR specific tumor uptake in MDA-MB-435 , U87MG and 4T1 xenograft models . The optimal tumor uptake was achieved at 2 h p.i. , which can be partially , but significantly blocked by co-injection of non-labeled scVEGF protein . Overall , [ (18)F]FBEM-scVEGF showed VEGFR specific tumor uptake.Conclusion : The scVEGF was site-specifically labeled with ( 18)F via [ (18)F]FBEM prosthetic group and the tracer [ (18)F]FBEM-scVEGF exhibited high receptor binding affinity and tumor targeting efficacy . Further study of [ (18)F ] FBEM-scVEGF to evaluate angiogenesis in cancer and other disease types is warranted . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot206

***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: Metastasis is a major cause of death of patients with malignant tumors . Matrix metalloproteinases ( MMPs ) are important for the migration and invasion of various types of cancer cell . Propofol is a known anesthetic agent , widely used for short-term anesthesia and for longer-term sedation . Propofol inhibits the proliferation of a variety of tumor cells , but there is no available information regarding propofol-inhibited migration and invasion of tumor cells in vitro . In this study , we investigated the effects of propofol on the migration and invasion of human lung carcinoma A549 cells . Wound healing assay and Boyden chamber assays indicated that propofol inhibited the migration and invasion of A549 cells in vitro . Gelatin zymographic analysis showed the inhibitory effect of propofol on the activation of expression MMP-2 . Western blot analysis also indicated that propofol suppressed the protein expiration of growth factor receptor-bound protein 2 ( GRB2 ) , Jun N-terminal kinases 1/2 ( p-JNK1/2 ) , p-p38 , MMP-2 and MMP-9 in A549 cells . Results from real-time PCR assay also showed that propofol inhibited the mRNA gene expression of MMP-2 , -7 and -9 , and enhanced that of tissue inhibitor of metalloproteinase 1 ( TIMP1 ) and TIMP2 in A549 cells . Taken together , these data show that propofol inhibits MMP-2 and -9 mRNA and protein expressions , resulting in suppression of lung cancer cell invasion and migration in vitro . OUTPUT: activating invasion and metastasis INPUT: OBJECTIVES The aim of this study was to immunohistochemically evaluate the expression of matrix metalloproteinase ( MMP)-1 , MMP- 2 , tissue inhibitor of metalloproteinase ( TIMP)-1 , TIMP-2 , and podoplanin in oral squamous cell carcinoma ( OSCC ) . Immunohistochemical staining of podoplanin-positive lymphatic vessel density ( LVD ) was also assessed . STUDY DESIGN Forty cases of OSCC were analyzed by immunohistochemistry . RESULTS MMP-2 , MMP-10 , TIMP-1 , TIMP-2 , and podoplanin were detected in each of the 40 OSCC cases . The expression of MMP-2 was significantly correlated with histologic grade . The expression of podoplanin was positively correlated with gender and negatively correlated with tumor size . A significant positive correlation was also detected between LVD and the presence of lymph node metastases , gender , age , and diameter of the lymph node ( if involved ) , as well as histologic grade . CONCLUSIONS The results are suggestive of important roles that MMP-2 , MMP-10 , TIMP-2 , and podoplanin play in pathologic processes of OSCC , including invasion . Our findings also suggest that LVD may play a role in lymphatic metastasis and tumor progression . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot207

***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: Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease ( LPD ) secondary to organ/bone marrow transplant-related immunosuppression ( 30 : 11 liver , 10 heart/lung , 8 kidney and 1 bone marrow ) , other drug-induced immunosuppression ( 2 ) , congenital immunodeficiency ( 8 ) or human immunodeficiency virus ( HIV)-related immune dysfunction ( 2 ) . Ages ranged from 10 months to 17 years and there were 15 girls . Pathology was centrally reviewed and showed polymorphic features in 5 cases , monomorphic in 23 , mixed pattern in 5 patients and 9 other types . Using the Revised European-American Classification of Lymphoid Neoplasms , 5 were B lymphoblastoid , 24 were high-grade B and 14 were other subtypes . Using the Pittsburgh classification , 9 were lymphadenopathic , 10 were systemic , 25 were lymphomatous and , with the Murphy grouping for non-Hodgkin's lymphoma ( NHL ) , 10 were localized and 32 non-localized . Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive . Thirty-five patients were evaluable for clonality ; 24 were monoclonal and 11 were polyclonal . Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24 , which was sustained in 11 . Nineteen patients received chemotherapy , 14/18 evaluable responded , which was sustained in 8 cases . Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died . In the largest group of patients , solid organ transplants , no significant clinical or biological characteristics that predicted outcome were identified . In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective . OUTPUT: avoiding immune destruction INPUT: Bone marrow necrosis ( BMN ) is a rare finding in children with malignancy occurring most commonly in children with acute lymphoblastic leukemia . This article describes the first case of a girl who developed BMN during treatment for Hodgkin's disease . During the second cycle of chemotherapy , she experienced sudden profound bone pain in the lumbosacral region associated with elevated levels of lactate dehydrogenase ( LDH ) , fibrin degradation products ( D-Dimer ) , and alkaline phosphatase as well as pancytopenia and leukoerythroblastosis . MRI studies showed multiple confluent areas with low signal intensity and rim contrast enhancement in all vertebral bodies . Bone marrow biopsy revealed focal necrosis within hypocellular bone marrow . The patient responded quickly to symptomatic treatment with analgetics and heparin ; however , elevations of LDH and D-Dimer persisted for 1.5 and 8 months , respectively . Clinicians should be aware of this rare condition to establish the diagnosis and to continue oncologic treatment as early as possible . OUTPUT:

resisting cell death

HoC_dynamic_1_shot208

***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 To assess the potential mechanisms that may underlie increased local failure in triple negative ( TN ) breast cancers , an analysis was performed of the risk of residual carcinoma after lumpectomy with correlation to pathologic factors , including molecular phenotype . METHODS A review of pathologic specimens was performed for women with invasive breast cancer treated with lumpectomy followed by reexcision . Data were collected on age ; tumor size , grade , and nodal stage ; estrogen receptor , progesterone receptor , and human endothelial growth factor receptor 2 ( Her2 ) ; extensive intraductal component ; lymphovascular invasion ; margins ; and reexcision findings . Univariate and multivariate logistic regression analyses were performed to evaluate for associations between pathologic features of the lumpectomy specimen and reexcision findings . Molecular phenotypes were defined by conventionally used immunohistochemical pattern . RESULTS Data were collected on 369 patients with breast cancer . The median age was 57 years , median tumor size was 1.5 cm , 36% had positive margins , 32% had positive lymph nodes , 73.5% had the luminal A subtype , 9.5% had the luminal B subtype , 4.5% were Her2-enriched , and 12.5% were TN . Overall , 32% of patients had invasive cancer in their reexcision specimens , and 51% of those with the TN subtype had residual invasive disease on reexcision compared with 30% to 31% for other subtypes . On univariate analysis , age , tumor size , margin status , lymphovascular invasion , nodal status , and TN subtype were associated with elevated risk of residual invasive cancer . On multivariate analysis using a forward stepwise model , TN subtype maintained significance , with an odds ratio of 3.28 ( P = .002 ) . CONCLUSION TN subtype has a statistically significant association with an increased risk of residual tumor . This suggests the putative increase in the risk of local failure in TN patients may be related to increased residual tumor burden . OUTPUT: activating invasion and metastasis INPUT: Background . Over the past ten years oncological outcomes achieved by local excision techniques ( LETs ) as the sole treatment for early stages of rectal cancer ( ESRC ) have been often disappointing . The reasons for these poor results lie mostly in the high risk of the disease's diffusion to local-regional lymph nodes even in ESRC . Aims . This study aims to find the correct indications for LET in ESRC taking into consideration clinical-pathological features of tumours that may reduce the risk of lymph node metastasis to zero . Methods . Systematic literature review and meta-analysis of casistics of ESRC treated with total mesorectal excision with the aim of identifying risk factors for nodal involvement . Results . The risk of lymph node metastasis is higher in G ≥ 2 and T ≥ 2 tumours with lymphatic and/or vascular invasion . Other features which have not yet been sufficiently investigated include female gender , TSM stage >1 , presence of tumour budding and/or perineural invasion . Conclusions . Results comparable to radical surgery can be achieved by LET only in patients with T(1) N(0) G(1) tumours with low-risk histological features , whereas deeper or more aggressive tumours should be addressed by radical surgery ( RS ) . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot209

***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: MicroRNAs ( miRNAs ) are small noncoding RNAs , 19-24 nucleotides in length , that regulate gene expression and are expressed aberrantly in most types of cancer . MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers . It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs . Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism , by binding as ligands to receptors of the Toll-like receptor ( TLR ) family , murine TLR7 and human TLR8 , in immune cells , triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis . Thus , by acting as paracrine agonists of TLRs , secreted miRNAs are key regulators of the tumor microenvironment . This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread , thus representing a possible target for cancer treatment . OUTPUT: activating invasion and metastasis;tumor promoting inflammation INPUT: MicroRNAs ( miRs ) are small non-coding RNAs that recently emerged as potent regulators of gene expression . The members of the miR-17-92 cluster have been shown to control endothelial cell functions and neovascularization ; however , the regulation and function of the cluster in endothelial cell lineage commitment has not been explored . This project aimed to test the role of the miR-17-92 cluster during endothelial differentiation . We demonstrate that miR-17 , miR-18 , miR-19 and miR-20 are increased upon the induction of endothelial cell differentiation of murine embryonic stem cells or induced pluripotent stem cells . In contrast , miR-92a and the primary miR-17-92 transcript were downregulated . The inhibition of each individual miR of the cluster by cholesterol-modified antagomirs did not affect endothelial marker gene expression . Moreover , the combination of all antagomirs had no effect . These findings illustrate that although the miR-17-92 cluster regulates vascular integrity and angiogenesis , none of the members has a significant impact on the endothelial differentiation of pluripotent stem cells . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot210

***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: Recent studies indicate that cyclooxygenase-2 ( COX-2 ) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer . A human pancreatic adenocarcinoma cell line , Mia PaCa-2 , was incubated for 18 hours with 5 micromol/L of rofecoxib ( Vioxx ) , a selective COX-2 inhibitor . Total RNA was isolated and gene expression analyzed by DNA microarray chips . In a separate experiment , athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy . After 1 month , laparotomy was repeated to measure tumor size , and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days . Tumor growth was assessed by comparing volume before and after treatment . In vitro , rofecoxib decreased gene expression of cyclin D1/PRAD1 , a key component of cell cycle progression , while increasing expression of several cell cycle arrest genes , including p21/WAF1 , p33/ING , GADD34 , and GADD45 ( P &lt ; 0.05 ) . In vivo , tumor growth was significantly reduced in treated vs. control mice ( P &lt ; 0.05 ) . No systemic toxicity was observed in mice receiving rofecoxib . These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: OBJECTIVE To evaluate the Expression and correlation of cyclooxygenase-2 ( COX-2 ) and vascular endothelial growth factor receptor ( VEGF ) in nasopharyngeal carcinoma . METHOD In this study , expression levels of COX-2 , VEGF were examined in 58 patients with nasopharyngeal carcinoma and 38 patients with inflammation in nasopharyngeal mucosa by immunohistochemistry method . RESULT The expression of COX-2 , VEGF were higher in nasopharyngeal carcinoma than those in nasopharyngeal mucosa ( P &lt ; 0.05 ) , and they had some correlation with the invasion and lymphatic metastasis and with the clinical stage of nasopharyngeal carcinoma ( P &lt ; 0.05 ) . The expression of COX-2 was positively correlated with that of VEGF ( P &lt ; 0.05 ) . CONCLUSION The coexpression of COX-2 and VEGF may play animportant role in the carcinogenesis and development of nasopharyngeal carcinoma , and they may prom ( see text ) lymph node metastasis of nasopharyngeal carcinoma . OUTPUT:

activating invasion and metastasis;inducing angiogenesis;tumor promoting inflammation;sustaining proliferative signaling

HoC_dynamic_1_shot211

***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: Tumor cells are surrounded by infiltrating inflammatory cells , such as lymphocytes , neutrophils , macrophages , and mast cells . A body of evidence indicates that mast cells are associated with various types of tumors . Although role of mast cells can be directly related to their granule content , their function in angiogenesis and tumor progression remains obscure . This study aims to understand the role of mast cells in these processes . Tumors were chemically induced in BALB/c mice and tumor progression was divided into Phases I , II and III . Phase I tumors exhibited a large number of mast cells , which increased in phase II and remained unchanged in phase III . The expression of mouse mast cell protease ( mMCP)-4 , mMCP-5 , mMCP-6 , mMCP-7 , and carboxypeptidase A were analyzed at the 3 stages . Our results show that with the exception of mMCP-4 expression of these mast cell chymase ( mMCP-5 ) , tryptases ( mMCP-6 and 7 ) , and carboxypeptidase A ( mMC-CPA ) increased during tumor progression . Chymase and tryptase activity increased at all stages of tumor progression whereas the number of mast cells remained constant from phase II to III . The number of new blood vessels increased significantly in phase I , while in phases II and III an enlargement of existing blood vessels occurred . In vitro , mMCP-6 and 7 are able to induce vessel formation . The present study suggests that mast cells are involved in induction of angiogenesis in the early stages of tumor development and in modulating blood vessel growth in the later stages of tumor progression . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot212

***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 cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology , contact inhibition and signal transduction during tumorigenesis . Protocadherin 8 ( PCDH8 ) , a member of the cadherin family , has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer . In this study , we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer . The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues . Methylation of the PCDH8 gene promoter was observed in 100% ( 4/4 ) of cell lines and 55.38% ( 36/65 ) of the primary gastric cancer by methylation-specific PCR , but not in normal gastric mucosa ( 0/10 ) . Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis . The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines . Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis . For the first time , our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer . Thus , PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer . OUTPUT: activating invasion and metastasis;resisting cell death INPUT: Semaphorin 5A , a member of semaphorin family , was originally identified as axonal guidance factor functioning during neuronal development . Previously , we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer . However , its functional roles and mechanism(s) in invasion and metastasis of gastric cancer remain unclear . By using human gastric caner cell lines Parental SGC7901 , SGC7901-siScrambled and SGC7901-siSema 5A , we found that semaphorin 5A significantly promoted the invasive and metastatic abilities of gastric cancer cell in vitro . Semaphorin 5A increased the expression of MMP9 by activating phosphorylated ErK1/2 in gastric cancer cell . Furthermore , MEK inhibitor PD98059 and MMP9 antibody ( Ab ) significantly inhibited in vitro invasive and metastatic abilities induced by semaphorin 5A . Taken together , the present work revealed a novel function of semaphorin 5A that the existence of semaphorin 5A could promote invasion and metastasis of gastric cancer by regulating MMP9 expression , at least partially , via the MEK/ERKs signal transduction pathway . Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy . OUTPUT:

activating invasion and metastasis;sustaining proliferative signaling

HoC_dynamic_1_shot213

***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: Recent evidence indicates that the estrogen receptor-α-negative , androgen receptor ( AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling . The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype ; its proliferation is stimulated by androgens such as 5α-dihydrotestosterone ( DHT ) but inhibited by the progestin medroxyprogesterone acetate ( MPA ) via AR-mediated mechanisms . We report here that the AR gene in MDA-MB-453 cells contains a G-T transversion in exon 7 , resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 ( Q865H ) in the ligand binding domain . Compared with wild-type AR , the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists . Ligand binding , molecular modeling , mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation , AR intramolecular interactions , and receptor stability . Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells . Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway . These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant . This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype . OUTPUT: sustaining proliferative signaling INPUT: Gadd45a , the first well-defined p53 downstream gene , can be induced by multiple DNA-damaging agents , which plays important roles in the control of cell cycle checkpoint , DNA repair process and signaling transduction . Our previous findings suggested that Gadd45a maintains cell-cell adhesion and cell contact inhibition . However , little is known about how Gadd45a participates in the suppression of malignancy in human cancer cells . To examine the functions of Gadd45a in cell invasion and metastasis , we performed the adhesion , wound-healing and transwell assays in Gadd45a ( +/+ ) and Gadd45a ( -/- ) MEF cell lines . We found the adhesion , migration and invasive abilities were much higher in Gadd45a deficient cells . We furthermore applied high-throughput cDNA microarray analysis and bioinformatics analysis to analyze the mechanisms of Gadd45a gene in invasion and metastasis . Compared with the Gadd45a wild type cells , the Gadd45a deficient cells showed a wide range of transcripts alterations . The altered gene pathways were predicted by the MAS software , which indicated focal adhesion,cell communication,ECM-receptor interaction as the three main pathways . Real-time PCR was employed to validate the differentially expressed genes . Interestingly , we figured out that the deregulations of these genes are caused neither by genomic aberrations nor methylation status . These findings provided a novel insight that Gadd45a may involve in tumor progression by regulating related genes expressions . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot214

***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 epithelial-mesenchymal transition ( EMT ) is a fundamental process governing morphogenesis in multicellular organisms and has recently been implicated in promoting carcinoma invasion and metastasis . Besides their therapeutic effects , accumulating evidences suggest that chemotherapeutic agents also induced EMT and enhanced the malignancy of treated cancer cells ; however , the mechanism(s) still remains unclear . Here , we investigated the role of β-catenin signaling in doxorubicin ( Dox)-induced EMT in human gastric cancer cell line BGC-823 . We found that the transient treatment of Dox induced EMT and enhanced the in vitro migration ability of cancer cells . We also found that β-catenin signaling was activated upon Dox treatment . Inhibition of β-catenin by indomethacin ( Indo ) or siRNA suppressed Dox-induced EMT and decreased cancer cell migration ability . Our results showed that β-catenin signaling was critical to Dox-induced EMT . Indo and other β-catenin inhibitors may have a potential implication in prevention of gastric cancer metastasis . OUTPUT: activating invasion and metastasis INPUT: Epithelial-to-mesenchymal transition ( EMT ) in cancer cells is considered to be a prerequisite for acquiring invasive/migratory phenotype and subsequent metastasis . This study provides molecular evidence associated with the antimetastatic effect of black tea polyphenol extracts ( BTE ) , which contain polyphenols including gallic acid , gallocatechin , catechin , epigallocatechin-3-gallate , epicatechin-3-gallate , and theaflavin 3,3'-digallate , in an an oral squamous cell culture system by showing a nearly complete inhibition on the invasion ( p &lt ; 0.001 ) of SCC-4 cells via reduced activities of MMP-2 ( p &lt ; 0.001 ) and u-PA ( p &lt ; 0.001 ) . Immunoblot was performed to find that BTE could induce up-regulation of epithelial markers such as E-cadherin and inhibit mesenchymal markers such as snail-1 and vimentin . BTE inhibited p-FAK and p-paxillin , indicating the anti-EMT effect of BTE in oral squamous cell carcinoma . BTE was evidenced by its inhibition of the tumor growth of SCC-4 cells via cancer cell xenografted nude mice mode . These results suggested that BTE could reduce invasion by reversing EMT in human oral cancer cells . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot215

***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 The study was designed to explore the effects of antisense human telomerase RNA ( ahTR ) on the malignant phenotype of gastric carcinoma cell line SGC-7901 , and its potential role in gene therapy for tumors . METHODS An ahTR eukaryotic expression vector , including the sequence of template region of telomere repeats , was constructed by recombinant technology of molecules and then transfected into gastric carcinoma cell line SGC-7901 by liposome DOTAP . Subsequently , the expression of hTR RNA and ahTR RNA by reverse transcription-polymerase chain reaction , telomerase activity by telomeric repeat amplification protocol-ELISA ( TRAP-ELISA ) , telomere length by Southern blotting , cell morphology under light microscope , cellular proliferation capacity by 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay , cell-cycle distribution by flow cytometry , efficiency of clone formation in soft agar , and tumorigenecity in nude mice were examined and evaluated in ahTR-transfected cells , control plasmid pCI-neo transfected cells and their parental cells . RESULTS An ahTR eukaryotic expression vector was constructed and successfully transfected into SGC-7901 cells . The telomerase activity in ahTR-transfected SGC-7901 cells decreased from 100% to approximately 25% , and telomere length in the cells shortened to 3.35 from 4.08 Kb at 60 population doublings . Compared with the parental cells and pCI-neo transfected cells , ahTR-transfected cells displayed some morphological changes , such as decreased atypia , and recovery of contact inhibition and density inhibition under light microscope . Furthermore , ahTR-transfected cells displayed decreased invasive capacity in Borden's chamber invasive model , increased G0/G1 phase rate and apoptotic rate . Surprisingly , ahTR-transfected SGC-7901 cells lost their capacity for clone formation in soft agar and tumorigencity in nude mice . CONCLUSION Antisense-hTR transfection can inhibit the growth of SGC-7901 cells and partially reverse the malignant phenotypes . This study provides an exciting approach for cancer therapy by inhibiting telomerase activity using an antisense gene . OUTPUT: evading growth suppressors;activating invasion and metastasis;resisting cell death INPUT: The Alternative Lengthening of Telomeres ( ALT ) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines . ALT is thought to involve templated extension of telomeres through homologous recombination , but the genetic or epigenetic changes that unleash ALT are not known . Recently , mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers , pediatric glioblastomas , and other tumors of the central nervous system , suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers . We have taken a comprehensive approach to deciphering ALT by applying genomic , molecular biological , and cell biological approaches to a panel of 22 ALT cell lines , including cell lines derived in vitro . Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines . In addition , ALT is associated with extensive genome rearrangements , marked micronucleation , defects in the G2/M checkpoint , and altered double-strand break ( DSB ) repair . These attributes will facilitate the diagnosis and treatment of ALT positive human cancers . OUTPUT:

enabling replicative immortality;genomic instability and mutation;evading growth suppressors

HoC_dynamic_1_shot216

***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: Lung cancer is the leading cause of cancer-related deaths in the world . Achaete-scute complex homolog-1 ( Ascl1 ) is a member of the basic helix-loop-helix ( bHLH ) transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation , prevention of apoptosis and promotion of tumor-initiating cells . We now show that Ascl1 directly regulates matrix metalloproteinase-7 ( MMP-7 ) and O(6)-methylguanine-DNA methyltransferase ( MGMT ) . Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1 , MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis . We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo . Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells , we found that there was a delay in lung tumorigenesis . We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance . The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis . OUTPUT: genomic instability and mutation;resisting cell death INPUT: In a screen for thoracic malignancy-associated markers , thyroid stimulating hormone receptor ( TSHR ) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1 . We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples . We found one patient with a somatic mutation at codon 458 ( exon 10 ) , which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases . This patient had lung adenocarcinoma with BAC ( bronchioloalveolar carcinoma ) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease ( COPD ) . In order to characterize the genetic features of TSHR in lung cancer , we checked for TSHR expression and copy number in the 96 lung cancer tissues . TSHR protein expression was generally overexpressed in multiple thoracic malignancies ( adenocarcinoma , squamous cell carcinoma and malignant pleural mesothelioma ) by immunohistochemistry . Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot217

***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: That a knock-in mouse harboring a dominant-negative thyroid hormone receptor ( TR)-β ( Thrb ) mutation develops metastatic thyroid cancer strongly suggests the involvement of TRβ in carcinogenesis . Epigenetic silencing of the THRB gene is common in human cancers . The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer ( DTC ) and how reexpression of the THRB gene attenuated the cancer phenotypes . We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues . Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5'-aza-2'-deoxycytidine ( 5'-aza-CdR ) and zebularine to evaluate their impact on the cancer cell phenotypes . THRB mRNA expression in DTC was 90% lower than in normal controls , and this decrease was associated with a higher tumor/lymph node staging . The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene . Treatment of FTC-236 cells with 5'-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration . FTC-236 cells stably expressing TRβ exhibited lower cell proliferation and migration through inhibition of β-catenin signaling pathways compared with FTC-236 without TRβ. 5'-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies . These finding indicate that TRβ is a tumor suppressor and could be tested as a potential therapeutic target . OUTPUT: activating invasion and metastasis;sustaining proliferative signaling INPUT: Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors . In addition , protons are a major constituent of the space radiation astronauts receive during space flights . The potential for these exposures to lead to , or enhance cancer risk has not been well studied . Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 ( TGFβ1)-mediated epithelial-mesenchymal transition ( EMT ) , a process occurring during tumor progression and critical for invasion and metastasis . Non-transformed mink lung epithelial cells ( Mv1Lu ) and hTERT- immortalized human esophageal epithelial cells ( EPC ) were used in this study . EMT was identified by alterations in cell morphology , EMT-related gene expression changes determined using real-time PCR , and EMT changes in specific cellular markers detected by immunostaining and western blotting . Although TGFβ1 treatment alone is able to induce EMT in both Mv1Lu and EPC cells , low energy protons ( 5 MeV ) at doses as low as 0.1 Gy can enhance TGFβ1 induced EMT . Protons alone can also induce a mild induction of EMT . SD208 , a potent TGFβ Receptor 1 ( TGFβR1 ) kinase inhibitor , can efficiently block TGFβ1/Smad signaling and attenuate EMT induction . We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition , more prominently in the presence of TGFβ1 , but also in the absence of TGFβ1 . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot218

***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: "Proliferating cells consume more glucose to cope with the bioenergetics and biosynthetic demands of rapidly dividing cells as well as to counter a shift in cellular redox environment . This study investigates the hypothesis that manganese superoxide dismutase ( MnSOD ) regulates cellular redox flux and glucose consumption during the cell cycle . A direct correlation was observed between glucose consumption and percentage of S-phase cells in MnSOD wild-type fibroblasts , which was absent in MnSOD homozygous knockout fibroblasts . Results from electron paramagnetic resonance spectroscopy and flow cytometric assays showed a significant increase in cellular superoxide levels in S-phase cells , which was associated with an increase in glucose and oxygen consumption , and a decrease in MnSOD activity . Mass spectrometry results showed a complex pattern of MnSOD-methylation at both lysine ( 68 , 89 , 122 , and 202 ) and arginine ( 197 and 216 ) residues . MnSOD protein carrying a K89A mutation had significantly lower activity compared with wild-type MnSOD . Computational-based simulations indicate that lysine and arginine methylation of MnSOD during quiescence would allow greater accessibility to the enzyme active site as well as increase the positive electrostatic potential around and within the active site . Methylation-dependent changes in the MnSOD conformation and subsequent changes in the electrostatic potential around the active site during quiescence versus proliferation could increase the accessibility of superoxide , a negatively charged substrate . These results support the hypothesis that MnSOD regulates a "" metabolic switch "" during progression from quiescent through the proliferative cycle . We propose MnSOD as a new molecular player contributing to the Warburg effect ." OUTPUT: cellular energetics;sustaining proliferative signaling;genomic instability and mutation INPUT: "BACKGROUND Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts . In the present study , we aimed to compare the mutation spectrum of 14 cancer genes , between these two phenotypes . METHODS A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "" hot spot "" regions of KRAS , BRAF , PIK3CA and NRAS , as well as selected mutations in CTNNB1 ( β-catenin ) , EGFR , FBXW7 ( CDC4 ) , PTEN , STK11 , MAP2K4 , SMAD4 , PIK3R1 and PDGFRA using a high-throughput genotyping technique . Additionally , APC was analyzed using direct sequencing . RESULTS APC mutations were more frequent in polypoid adenomas compared to flat adenomas ( 48.5% versus 30.3% , respectively , p = 0.02 ) . Mutations in KRAS , BRAF , NRAS , FBXW7 and CTNNB1 showed similar frequencies in both phenotypes . Between the different subtypes of flat adenomas ( 0-IIa , LST-F and LST-G ) no differences were observed for any of the investigated genes . CONCLUSION The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes . Furthermore , in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway ." OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot219

***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: EBV latent antigen EBNA3C is indispensible for in vitro B-cell immortalization resulting in continuously proliferating lymphoblastoid cell lines ( LCLs ) . EBNA3C was previously shown to target pRb for ubiquitin-proteasome mediated degradation , which facilitates G1 to S transition controlled by the major transcriptional activator E2F1 . E2F1 also plays a pivotal role in regulating DNA damage induced apoptosis through both p53-dependent and -independent pathways . In this study , we demonstrate that in response to DNA damage LCLs knocked down for EBNA3C undergo a drastic induction of apoptosis , as a possible consequence of both p53- and E2F1-mediated activities . Importantly , EBNA3C was previously shown to suppress p53-induced apoptosis . Now , we also show that EBNA3C efficiently blocks E2F1-mediated apoptosis , as well as its anti-proliferative effects in a p53-independent manner , in response to DNA damage . The N- and C-terminal domains of EBNA3C form a stable pRb independent complex with the N-terminal DNA-binding region of E2F1 responsible for inducing apoptosis . Mechanistically , we show that EBNA3C represses E2F1 transcriptional activity via blocking its DNA-binding activity at the responsive promoters of p73 and Apaf-1 apoptosis induced genes , and also facilitates E2F1 degradation in an ubiquitin-proteasome dependent fashion . Moreover , in response to DNA damage , E2F1 knockdown LCLs exhibited a significant reduction in apoptosis with higher cell-viability . In the presence of normal mitogenic stimuli the growth rate of LCLs knockdown for E2F1 was markedly impaired ; indicating that E2F1 plays a dual role in EBV positive cells and that active engagement of the EBNA3C-E2F1 complex is crucial for inhibition of DNA damage induced E2F1-mediated apoptosis . This study offers novel insights into our current understanding of EBV biology and enhances the potential for development of effective therapies against EBV associated B-cell lymphomas . OUTPUT: genomic instability and mutation;resisting cell death INPUT: BACKGROUND Epstein-Barr virus ( EBV ) encodes six nuclear transformation-associated proteins that induce extensive changes in cellular gene expression and signaling and induce B-cell transformation . The role of HIF1A in EBV-induced B-cell immortalization has not been previously studied . METHODS AND FINDINGS Using Western blotting and Q-PCR , we found that HIF1A protein is stabilized in EBV-transformed lymphoblastoid cells . Western blotting , GST pulldown assays , and immunoprecipitation showed that EBV-encoded nuclear antigens EBNA-5 and EBNA-3 bind to prolylhydroxylases 1 and 2 , respectively , thus inhibiting HIF1A hydroxylation and degradation . Immunostaining and Q-PCR showed that the stabilized HIF1A translocates to the nucleus , forms a heterodimer with ARNT , and transactivates several genes involved in aerobic glycolysis . Using biochemical assays and Q-PCR , we also found that lymphoblastoid cells produce high levels of lactate , lactate dehydrogenase and pyruvate . CONCLUSIONS Our data suggest that activation of the aerobic glycolytic pathway , corresponding to the Warburg effect , occurs in EBV-transformed lymphoblastoid cells , in contrast to mitogen-activated B-cells . OUTPUT:

cellular energetics

HoC_dynamic_1_shot220

***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: Histone deacetylase inhibitors ( HDACi ) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use . In this study , we tested using in vitro and in vivo models the differential biological effects of a novel HDAC inhibitor [ belinostat ( PXD101) ] , in a wide panel of androgen-sensitive and androgen-independent tumor cells . Belinostat significantly increased acetylation of histones H3 and H4 . Belinostat potently inhibited the growth of prostate cancer cell lines ( IC50 range from 0.5 to 2.5 �M ) with cytotoxic activity preferentially against tumor cells . This agent induced G2/M arrest and increased significantly the percentage of apoptosis mainly in androgen-sensitive tumor cells confirming its growth-inhibitory effects . The cell death mechanisms were studied in three different prostate cancer cell lines with different androgen dependence and expression of androgen receptor ; LAPC-4 and 22rv1 ( androgen-dependent and expressing androgen receptor ) and PC3 ( androgen-independent not expressing androgen receptor ) . Belinostat induced the expression of p21 and p27 , acetylation of p53 and G2/M arrest associated with Bcl2 and Bcl-Xl downmodulation and significant reduction of survivin , IAPs and Akt/pAkt and increased caspase-8 and -9 expression/activity . Belinostat effectiveness was dependent on the androgen receptor ( AR ) , since the stable transfection of AR greatly increased the efficacy of this HDAC inhibitor . These observations were correlated using in vivo models . We demonstrated that belinostat preferentially resulted in antitumor effect in androgen-dependent tumor cells expressing AR . Our findings provide evidence that belinostat may be a promising anticancer drug for prostate cancer expressing AR , supporting its clinical role in prostate cancer . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: Stress-induced phosphoprotein 1 ( STIP1 ) , a cochaperone that organizes other chaperones , heat shock proteins ( HSPs ) , was recently shown to be secreted by human ovarian cancer cells . In neuronal tissues , binding to prion protein was required for STIP1 to activate the ERK ( extracellular-regulated MAP kinase ) signaling pathways . However , we report that STIP1 binding to a bone morphogenetic protein ( BMP ) receptor , ALK2 ( activin A receptor , type II-like kinase 2 ) , was necessary and sufficient to stimulate proliferation of ovarian cancer cells . The binding of STIP1 to ALK2 activated the SMAD signaling pathway , leading to transcriptional activation of ID3 ( inhibitor of DNA binding 3 ) , promoting cell proliferation . In conclusion , ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways . Although animal studies are needed to confirm these mechanisms in vivo , our results may pave the way for developing novel therapeutic strategies for ovarian cancer . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot221

***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: It has been shown that injecting a suspension of IFN-γ-secreting tumor cells results in their rejection . This effect has been attributed to IFN-γ preventing tumor stroma formation but not to a direct effect on the cancer cells . However , it is not known , which influence IFN-γ has on tumors with an established stroma . To address this question , the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-γ gene expression . After the injection of the tumor cells into mice , IFN-γ was induced at different time points . Tumors did not grow when inducing IFN-γ immediately after tumor cell inoculation , while approximately half of the tumors were rejected when IFN-γ was induced in early established tumors within 2 weeks . Induction of IFN-γ 2-3 weeks after tumor cell inoculation was less efficient ( 0-17% rejection ) . IFN-γ induction in established tumors led to a reduction of CD146(+) endothelial cells and massive necrosis . Together , we show that vascularized tumors can be rejected by local IFN-γ expression , but that rejection of established tumors was less efficient over time . This suggests that transplanted tumors became less susceptible to local IFN-γ treatment the better they are established . OUTPUT: resisting cell death;inducing angiogenesis INPUT: IFN-γ is a master regulator of the immune responses that occur in the transplanted kidney , acting both on the immune system and on the graft itself . The cellular responses to IFN-γ are complex , and emerging evidence suggests that IFN-γ may regulate autophagic functions . Conversely , autophagy modulates innate and adaptive immune functions in various contexts . In this study , we identify a novel mechanism by which IFN-γ activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-γ . Our results indicate that IFN-γ promotes tryptophan depletion , activates the eIF2α kinase general control nonderepressible-2 ( GCN2 ) , and leads to an increase in the autophagic flux . Further , tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-γ-induced autophagy . This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-γ . These findings assign to IFN-γ a novel function in the regulation of autophagy , which , in turn , modulates IFN-γ-induced secretion of inflammatory cytokines . OUTPUT:

resisting cell death;tumor promoting inflammation

HoC_dynamic_1_shot222

***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 constitutes a major health problem for women worldwide . However , its incidence varies between populations and geographical locations . These variations could be diet-related , since there are several carcinogenic compounds in the modern diet , while natural products contain various anti-cancer elements . Several lines of evidence indicate that , in addition to their clear preventive effect , these compounds could also be used as therapeutic agents . In the present report we have shown that oleuropein , a pharmacologically safe natural product of olive leaf , has potent anti-breast cancer properties . Indeed , oleuropein exhibits specific cytotoxicity against breast cancer cells , with higher effect on the basal-like MDA-MB-231 cells than on the luminal MCF-7 cells . This effect is mediated through the induction of apoptosis via the mitochondrial pathway . Moreover , oleuropein inhibits cell proliferation by delaying the cell cycle at S phase and up-regulated the cyclin-dependent inhibitor p21 . Furthermore , oleuropein inhibited the anti-apoptosis and pro-proliferation protein NF-κB and its main oncogenic target cyclin D1 . This inhibition could explain the great effect of oleuropein on cell proliferation and cell death of breast cancer cells . Therefore , oleuropein warrants further investigations to prove its utility in preventing/treating breast cancer , especially the less-responsive basal-like type . OUTPUT: resisting cell death;evading growth suppressors;sustaining proliferative signaling INPUT: Breast cancer metastasis is the most common cause of cancer-related death in women . Thus , seeking targets of breast tumor cells is an attractive goal towards improving clinical treatment . The present study showed that CCL18 from tumor-associated macrophages could promote breast cancer metastasis via PITPNM3 . In addition , we found that pachymic acid ( PA ) could dose-dependently inhibit migration and invasion of MDA-MB-231 cells , with or without rCCL18 stimulation . Furthermore , evidence was obtained that PA could suppress the phosphorylation of PITPNM3 and the combination of CCL18 and PITPNM3 . Therefore , we speculate that PA could inhibit breast cancer metastasis via PITPNM3 . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot223

***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: Androgen receptor ( AR ) signals have been suggested to contribute to bladder tumorigenesis and cancer progression . Activation of epidermal growth factor receptor ( EGFR ) also leads to stimulation of bladder tumor growth . However , crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized . We have recently shown that androgens activate the EGFR pathway in bladder cancer cells . The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer . EGF increased AR transcriptional activity by 1.2- , 1.9- and 2.0-fold in UMUC3 , 5637-AR and J82-AR cell lines , respectively , over mock treatment and a specific EGFR inhibitor , PD168393 , antagonized the EGF effect . Combined treatment of EGF and dihydrotestosterone ( DHT ) further induced AR transactivation while an AR antagonist , hydroxyflutamide ( HF ) , abolished the effect of not only DHT but also EGF . In growth assays , EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19% , 6/14/18% and 30/12/38% in UMUC3-control-shRNA , 5637-AR and J82-AR , respectively , whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA ( 8% ) or AR-negative 5637-V ( <1% ) and J82-V ( 17% ) cells . HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells . Western blotting demonstrated that EGF , especially in the presence of DHT , upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation . Co-immunoprecipitation revealed the association between AR and estrogen receptor ( ER)-β or Src in UMUC3 cells and stronger associations with EGF treatment , implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth . Current results , thus , suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals . Taken together with our previous findings , crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer . OUTPUT:

sustaining proliferative signaling

HoC_dynamic_1_shot224

***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: It is still difficult to decide on the treatment modalities for advanced esophageal carcinoma when the prognostic factors of T4 esophageal cancer are not fully understood . In this article , we report that among 71 patients with T4 thoracic esophageal cancer , 49 underwent esophagectomy , 9 had curative resection ( R0 group ) , and 40 had palliative resection ( R1/2 group ) . A total of 22 patients had palliative treatments : bypass in 5 ( bypass group ) , gastrostomy or jejunostomy in 6 ( stoma group ) , and radiochemotherapy alone in 11 ( nonoperation group ) . Clinicopathologic characteristics were retrospectively investigated . Treatment-related deaths occurred in 7 ( 10% ) : none in R0 , 3 ( 8% ) in R1/2 , 3 ( 60% ) in bypass , and 1 ( 17% ) in stoma group . Swallowing was improved in 50 ( 70% ) patients : 9 ( 100% ) in R0 , 30 ( 75% ) in R1/2 , 1 ( 20% ) in bypass , 3 ( 50% ) in stoma , and 7 ( 64% ) in the nonoperation group . One- , two- , and three-year overall survival rates were 56% , 22% , and 22% in the R0 group and 35% , 19% and 6% in the R1/2 group , respectively ( p = 0.19 ) . In the bypass , stoma , and nonoperation groups , none survived 1.6 years . The factors influencing the survival rate of the 49 patients undergoing esophagectomy were grade of lymph node metastasis , amount of perioperative blood transfusion , lymph vessel , and blood vessel invasion . Among these , independent prognostic factors for survival were amount of blood transfusion ( -6 units vs. -7 units , p <0.0001 ) and grade of lymph node metastasis [ none- or peritumoral [ lymph nodes adjacent to the main tumor or at a nearby location ( <3 cm ) from the tumor ] metastasis vs. more distant metastasis [ lymph nodes at a distant location ( &gt ; 3 cm) ] , p = 0.016 ] . Bypass and stoma operation neither prolonged the survival nor improved the difficulty of swallowing compared with radiochemotherapy alone . Esophagectomy can achieve the best improvement of swallowing and the longest survival with an acceptable mortality rate . Esophageal carcinoma patients with T4 disease and distinct metastasis in the lymph nodes at a distant location ( >3 cm ) from the primary tumor may not benefit from an esophageal resection . OUTPUT: activating invasion and metastasis INPUT: Multiple endocrine neoplasia type 2 ( MEN2 ) is an autosomal , dominantly inherited disease characterized by medullary thyroid carcinoma , pheochromocytoma , and primary hyperparathyroidism and is divided into types 2A and 2B . Familial medullary thyroid carcinoma ( FMTC ) is characterized by the presence of medullary thyroid carcinoma alone in family members and is considered to be one of the subtypes of MEN2 . Clinical and genetic data on 505 Japanese patients from 275 MEN2 or FMTC families registered at 54 medical institutions were collected by the MEN Consortium of Japan . The diagnosis was MEN2A in 343 ( 67.9% ) patients , MEN2B in 29 ( 5.7% ) , FMTC in 103 ( 20.4% ) , and unclassified in 30 ( 5.9% ) . Medullary thyroid carcinoma was found in 91.2% of patients ( 437/479 ) , pheochromocytoma in 45.6% ( 212/465 ) , and primary hyperparathyroidism in 8.1% ( 37/457 ) . RET genetic testing was performed in 410 patients , and the germline RET mutation was found in 98.8% ( 397/402 ) . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot225

***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: Focal inflammation causes systemic fever . Cancer hyperthermia therapy results in shrinkage of tumors by various mechanisms , including induction of adaptive immune response . However , the physiological meaning of systemic fever and mechanisms of tumor shrinkage by hyperthermia have not been completely understood . In this study , we investigated how heat shock influences the adaptive immune system . We established a cytotoxic T lymphocyte ( CTL ) clone ( #IM29 ) specific for survivin , one of the tumor-associated antigens ( TAAs ) , from survivin peptide-immunized cancer patients ' peripheral blood , and the CTL activities were investigated in several temperature conditions ( 37-41�C ) . Cytotoxicity and IFN-γ secretion of CTL were greatest under 39�C condition , whereas they were minimum under 41�C . To address the molecular mechanisms of this phenomenon , we investigated the apoptosis status of CTLs , expression of CD3 , CD8 , and TCRαβ by flow cytometry , and expression of perforin , granzyme B , and Fas ligand by western blot analysis . The expression of perforin and granzyme B were upregulated under temperature conditions of 39 and 41�C . On the other hand , CTL cell death was induced under 41�C condition with highest Caspase-3 activity . Therefore , the greatest cytotoxicity activity at 39�C might depend on upregulation of cytotoxic granule proteins including perforin and granzyme B. These results suggest that heat shock enhances effector phase of the adaptive immune system and promotes eradication of microbe and tumor cells . OUTPUT: resisting cell death INPUT: Background/Aims : Cimetidine has been shown to play an important role in the treatment of cancer and the regulation of the immune system . Therefore , we aimed to observe the effects of cimetidine on the systematic immune response in the perioperative period . Methodology : Sixty patients with colorectal cancer were enrolled from Jan 2005 to Dec 2005 from Taizhou Hospital . The patients were administrated with cimetidine ( 0.8g�d-1 or 1.2g�d-1 ) or saline from the day of admission to the 10th POD . Venous blood sample was collected and the T- , B- and NK-lymphocyte subsets were determined by flow cytometry . The specimens were subjected to tumor-infiltrating lymphocytes ( TILs ) response examination . Results : The levels of CD3 and CD4 T-lymphocytes were increased significantly in both low and high dose cimetidine groups 10 days after operation . The number of CD19 B cells was also elevated by cimetidine . However , no significant changes were observed in the CD8 , CD4/CD8 value . TIL responses in the cimetidine groups were also enhanced significantly . Conclusions : Cimetidine can alleviate systematic immunosuppression and improve the local immune function of the colorectal cancer patients in the perioperative period . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot226

***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: Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer , and to date no therapies exist targeting this oncogene . K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways , and much effort has been focused on developing drugs targeting components of these pathways . To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance , we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors . Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested , demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors . We further examined signaling downstream of K-RAS , and detected a robust reduction of pERK levels upon K-RAS knock down . In contrast , no effect on pAKT levels could be observed due to almost undetectable basal expression levels . To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance , three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition . Tumors of all three models regressed upon MEK inhibition , but showed less pronounced response to PI3K inhibition . The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor . These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot227

***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 presence of distant metastases from colorectal cancer ( CRC ) does not preclude curative treatment . Early detection of pulmonary metastases at a potentially curable stage could improve survival . The aim of the present study was to assess the prognostic significance of commonly reported clinicopathologic features to identify high-risk patients who would likely benefit from more intensive chest surveillance for pulmonary metastases . MATERIAL AND METHOD A total of 351 consecutive patients , with surgical stages I-III colorectal cancer , who underwent curative resection at Phramongkutklao hospital from 1999 to 2005 , were followed regularly according to the established guidelines with routine physical examination , serum carcinoembryonic antigen ( CEA ) and colonoscopic surveillance . Imaging studies for detecting metastases were computed tomography ( CT ) , plain film radiography , and ultrasonograpy . Clinical and pathologic features were analyzed for their association with pulmonary metastasis . RESULTS There were 145 patients who had been operated for longer than five years after curative intent surgery . Of these , nineteen patients were lost to follow-up or died from other causes that were unrelated to colorectal cancer . Pulmonary metastases were detected in 26 patients by either CXR or CT scan . Median time to pulmonary metastasis was 19 months ( 95 percent CI , 12-35 ) . According to an univariate analysis , with log-rank test , identified four factors associated with pulmonary metastasis : Tumor stage T4 , Nodal stage N2 , elevation of serum CEA &gt ; 3.4 ng/ml and presence of lymphovascular invasion(LVI) . According to a multivariate analysis , with Cox regression , found an elevation of serum CEA &gt ; 3.4 ng/ml which was an independent factor that was significantly associated with pulmonary metastasis ( Hazard ratio ( HR ) , 8.9 ; 95 percent CI , 3.6-22 ; p &lt ; 0.01 ) . The present study revealed that 50 percent of patients who had more than one of these risk factors would eventually develop pulmonary metastases . CONCLUSION An elevation of serum CEA &gt ; or = 3.4 ng/ml was found as an independent factor that was significantly associated with pulmonary metastasis whereas tumor stage T4 , nodal stage N2 and presence of lymphovascular invasion ( LVI ) were not independent clinicopathologic features associated with subsequent pulmonary metastases . Chest CT scan has greater sensitivity than chest radiography in detection of pulmonary metastasis and should be considered as an imaging study of choice for intensive chest surveillance for patients who had more than one of these risk factors . OUTPUT: activating invasion and metastasis INPUT: BACKGROUND Γ-Ionizing radiation ( IR ) therapy is one of major therapeutic tools in cancer treatment . Nevertheless , γ-IR therapy failed due to occurrence of metastasis , which constitutes a significant obstacle in cancer treatment . The main aim of this investigation was to construct animal model which present metastasis during radiotherapy in a mouse system in vivo and establishes the molecular mechanisms involved . MATERIALS AND METHODS The C6L transfectant cell line expressing firefly luciferase ( fLuc ) was treated with γ-IR , followed by immunoblotting , zymography and invasion assay in vitro . We additionally employed the C6L transfectant cell line to construct xenografts in nude mice , which were irradiated with γ-IR . Irradiated xenograft-containing mice were analyzed via survival curves , measurement of tumor size , and bioluminescence imaging in vivo and ex vivo . Metastatic lesions in organs of mice were further assessed using RT-PCR , H &amp ; E staining and immunohistochemistry . RESULTS γ-IR treatment of C6L cells induced epithelial-mesenchymal transition ( EMT ) and increased cell invasion . In irradiated xenograft-containing mice , tumor sizes were decreased dramatically and survival rates extended . Almost all non-irradiated xenograft-containing control mice had died within 4 weeks . However , we also observed luminescence signals in about 22.5% of γ-IR-treated mice . Intestines or lungs of mice displaying luminescence signals contained several lesions , which expressed the fLuc gene and presented histological features of cancer tissues as well as expression of EMT markers . CONCLUSIONS These findings collectively indicate that occurrences of metastases during γ-IR treatment accompanied induction of EMT markers , including increased MMP activity . Establishment of a murine metastasis model during γ-IR treatment should aid in drug development against cancer metastasis and increase our understanding of the mechanisms underlying the metastatic process . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot228

***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: p53 is a tumor suppressor gene that is mutated in many human malignancies , including gastric cancer . It remains unclear why patients with germ-line p53 mutations ( i.e. , Li-Fraumeni syndrome ) are not at increased risk for gastric adenocarcinoma , despite the fact that they show a high rate of many other tumors . Furthermore , the precise relationship between germ-line p53 mutations and the response to chronic bacterial infections ( such as Helicobacter spp. ) has not been investigated . To assess the role of germ-line p53 deletions in modulating the progression to gastric cancer , p53(+/-) and wild-type ( WT ) C57BL/6 mice were infected with H. felis . The gastric pathology and immune response in these two groups of mice were analyzed for up to 15 months postinfection . The gastric fundus and antrum were evaluated independently using a 0-4 scale to score inflammation , parietal and chief cell loss , mucus metaplasia , and helicobacter colonization . Nonparametric statistical analysis was performed to determine the effects of p53(+/-) , infection status , and postinoculation ( p.i. ) time on inflammation , preneoplastic changes , invasive lesions , and helicobacter colonization. mRNA expression for gammaIFN , interleukin ( IL)-1 , IL-10 , and IL-4 was quantified by PCR . Sera were also evaluated for H. felis antibody by ELISA . Antral inflammation increased significantly with time in infected mice . There was a significant , protective effect on the development of preneoplastic fundic lesions and invasive carcinoma attributable to the deletion of one p53 allele ( P &lt ; 0.05 ) . Submucosal invasive foci were observed in 9 of 11 WT-infected mice ranging from 13 to 15 months p.i. ; invasion of adjacent submucosal blood vessels by glandular epithelia also was present in 5 of these mice . None of these lesions were observed in 33 p53(+/-) mice , infected or not , at any time p.i. p53(+/-) mice had significantly higher helicobacter colonization consistent with a Th2 host response . In sera from WT mice , IgG2a , considered a proinflammatory Th1 response , continued to rise throughout the 15-month study ( P &lt ; 0.004 ) . In contrast , IgG2a levels of the p53(+/-) mice were 50-60% lower than those of the WT mice at each time point ( P range , <0.012 to 0.002 ) and did not progress in magnitude between 12 and 15 months of chronic H. felis infection ( P = 0.167). mRNA levels for gammaIFN and IL-1 were significantly up-regulated in WT mice infected with H. felis ( P &lt ; 0.05 ) but were slightly elevated or were at background levels in p53(+/-) mice . IL-10 and IL-4 mRNA expression was not significantly different from control samples . Our results support the hypothesis that germ-line deletion of one p53 allele results in a down-regulated Th1 response to gastric helicobacter infection , possibly because of T-cell senescence , which may indirectly protect against the development of gastric cancer and other epithelial-derived neoplasms associated with chronic inflammation . OUTPUT: tumor promoting inflammation;activating invasion and metastasis;enabling replicative immortality INPUT: RASSF2 has recently been identified as a potential tumor suppressor that serves as a Ras effector in various types of human cancers . However , there have been few reports detailing this in gastric cancer . Samples of gastric adenocarcinoma from 276 Chinese patients with follow-up were analyzed for RASSF2 protein expression by immunohistochemistry . RASSF2 was expressed in up to 31.2% ( 86/276 ) of this group of gastric carcinoma . The expression of RASSF2 was significantly lower in carcinomas than in normal mucosas ( P<0.05 ) . RASSF2 corresponded positively with patient age , histological differentiation , depth of tumor invasion , regional lymph node and distant metastasis , and TNM stage ( all P<0.05 ) . Further multivariate analysis revealed that patient gender , depth of tumor invasion , distant metastasis , TNM stage and the expression of RASSF2 were independent prognostic factors for patients with gastric cancer . The Kaplan-Meier plot showed that the overall mean survival time of the patients with RASSF2-negative expression was shorter than that of patients with positive expression ( χ(2)=156.874 , P<0.0001 ) . Moreover , RASSF2-negative expression had a much more significant effect on the survival of those patients with early stage tumors ( χ(2)=127.167 , P<0.0001 ) , highlighted by a >50.9% reduction in 3-year survival compared to that of patients with RASSF2-positive expression . In late stages , the difference was also significant ( χ(2)=6.246 , P=0.019 ) , with a 35.5% reduction in 3-year survival . It is suggested that RASSF2 plays an important role in the evolution of gastric adenocarcinoma and should be considered as a potential marker for its prognosis . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot229

***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-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors . Consequently , the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types . In addition to host immune responses , intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance , metastatic dissemination and the induction of immune suppression . Cancer stem cells are far from a static cell population ; rather , their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma . However , the impact immune responses have on tumor stem cell differentiation or expansion is not well understood . In this study , we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors . Targeting CCR2 or CSF1R improves chemotherapeutic efficacy , inhibits metastasis and increases antitumor T-cell responses . Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3 , thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes . Together , our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells . OUTPUT: tumor promoting inflammation;activating invasion and metastasis;avoiding immune destruction INPUT: Macrophages are the prominent components of solid tumors and have complex dual functions in their interaction with cancer cells . Strong evidence suggests that TAM is a part of inflammatory circuits that promote tumor progression . B7-homologue 3 ( B7-H3 ) , a recently identified homologue of B7.1/2 ( CD80/86 ) , has been described to exert co-stimulatory and immune regulatory functions . Here , we showed that a fraction of macrophages in tumor stroma expressed surface B7-H3 molecule . Normal macrophages , which did not express B7-H3 , would be induced expressing B7-H3 molecule when culturing with tumor cell . Although a lung cancer cell line constitutively expressed B7-H3 mRNA and protein in plasma , primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H3 on the surface . Interestingly , in transplanted lung carcinoma model , the expression of membrane-bound B7-H3 in tumor cells was increased as prolonging of tumor transformation . In support , IL-10 released from TAM could stimulate cancer cell expression of membrane bound B7-H3 . Furthermore , Lung cancer and TAM-related B7-H3 was identified as a strong inhibitor of T-cell effect and influenced the outcome of T cell immune response . In conclusion , TAM-tumor cell interaction-induced membrane-bound B7-H3 represents a novel immune escape mechanism which links the pro-inflammatory response to immune tolerance in the tumor milieu . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot230

***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 : Emerging evidences implicate long noncoding RNAs ( lncRNAs ) are deregulated in cancer development . The purpose of the current study is to investigate the role of new lncRNA , named PlncRNA-1 , in prostate cancer ( CaP ) pathogenesis . MATERIALS AND METHODS : In this study , real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues , 14 pairs CaP tissues and BPH tissues , 4 CaP cell lines , including LNCaP , LNCaP-AI , PC3 , and C4-2 , and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E . After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines , cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling ( TUNEL ) . After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines , real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR . RESULTS : We showed that expression PlncRNA-1 , was significantly higher in CaP cells relative to normal prostate epithelial cells , as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia ( BPH ) . Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI . Mechanistically , PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor ( AR ) mRNA , protein and AR downstream target . Of note , blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines . CONCLUSIONS : Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: OBJECTIVES Human neutrophil proteins-1 , -2 , and -3 ( HNPs -1 , -2 , and -3 ) are expressed in several tumor types . However , the role of HNPs 1-3 in human bladder cancer has not yet been determined . We investigated the association between the plasma levels of HNPs 1-3 and clinicopathological parameters in bladder cancer patients . DESIGN AND METHODS The plasma levels of HNPs 1-3 were measured in 60 patients with bladder cancer and in 58 healthy controls . The plasma levels of HNPs 1-3 were determined by a solid-phase enzyme-linked immunosorbent assay ( ELISA ) . Plasma samples were obtained before surgery . Plasma samples were permitted to clot and were then stored at -80 �C until use . RESULTS The levels of the HNPs increased from grade 1 to 4 tumors and this difference was statistically significant ( p &lt ; 0.001 ) . Additionally , plasma HNP levels were significantly higher in patients with metastatic bladder cancer and in patients with lymphovascular involvement , metastasis of the lymph nodes , and increased tumor burden ( p &lt ; 0.001 ) . CONCLUSIONS The preoperative plasma levels of HNPs 1-3 paralleled the progression and pathological stages of the malignancies . This study suggests that HNPs 1-3 promote tumor invasion and are potential indicators of disease progression in patients with bladder cancer . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot231

***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: Angiogenesis , the formation of new blood vessels from pre-existing vascular beds , is essential for tumor growth , invasion , and metastasis . Luteolin is a common dietary flavonoid found in fruits and vegetables . We studied the antiangiogenic activity of luteolin using in vitro , ex vivo , and in vivo models . In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation , migration , invasion and tube formation of endothelial cells , which are key events in the process of angiogenesis . Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay ( CAM ) and matrigel plug assay . Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9 . Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT , ERK , mTOR , P70S6K , MMP-2 , and MMP-9 in HUVECs . Proinflammatory cytokines such as IL-1β , IL-6 , IL-8 , and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells . Luteolin ( 10 mg/kg/d ) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model , indicating that luteolin inhibited tumorigenesis by targeting angiogenesis . CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin . Moreover , luteolin reduced cell viability and induced apoptosis in prostate cancer cells , which were correlated with the downregulation of AKT , ERK , mTOR , P70S6K , MMP-2 , and MMP-9 expressions . Taken together , our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis . OUTPUT: inducing angiogenesis;resisting cell death INPUT: Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus , a medicinal plant that possesses antitumorigenic properties . Our previous findings demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells . In the present study , we aimed to further examine the potential of formononetin in controlling angiogenesis and tumor cell invasiveness in human colon cancer cells and tumor xenografts . The results showed that formononetin downregulated the expression of the key pro-angiogenic factors , including vascular endothelial growth factor ( VEGF ) and matrix metalloproteinases . We also discovered that the invasiveness of metastatic colon cancer cells was alleviated following drug treatment . The potential anti-angiogenic effect of formononetin was examined in nude mouse xenografts . The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group . The serum VEGF level was also reduced in the drug-treated animals when compared to the controls . These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion , and thus support its use in the treatment of advanced and metastatic colon cancers . OUTPUT:

inducing angiogenesis;activating invasion and metastasis

HoC_dynamic_1_shot232

***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 Angiogenesis represents a key element in the pathogenesis of malignancy . There are no robust data on prognostic factors for overall survival ( OS ) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor ( VEGF)-targeted therapy . The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer . METHODS Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers . Cox proportional hazards regression was used to identify independent prognostic factors for OS . RESULTS The median OS for the whole cohort was 19 months ( 95% CI , 14.3 to 23.6 months ) . Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology ( ASMO ) were independent predictors of short survival : serum lactate dehydrogenase ( LDH ) greater than the upper limit of normal ( ULN ; p<0.001 ) ; neutrophils greater than the ULN ( p<0.0014 ) ; and progression free survival ( PFS ) less than 6 months ( p =0.001 ) . CONCLUSION Serum LDH and neutrophil levels were the main prognostic factors in predicting survival , followed by PFS . This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents . OUTPUT: inducing angiogenesis INPUT: BACKGROUND Angiogenic factors following oncological surgery is important in tumor recurrence . Vascular endothelial growth factor ( VEGF ) , angiopoietin 1 ( Ang-1 ) , Ang-2 , soluble VEGF-receptor 1 ( sVEGFR1 ) and sVEGFR2 may influence angiogenesis . This prospective study examined the influence of open and video-assisted thoracic surgery ( VATS ) lung resections for early stage non-small cell lung cancer ( NSCLC ) on postoperative circulating angiogenic factors . METHODS Forty-three consecutive patients underwent major lung resection through either VATS ( n = 23 ) or Open thoracotomy ( n = 20 ) over an 8-month period . Blood samples were collected preoperatively and postoperatively on days ( POD ) 1 and 3 for enzyme linked immunosorbent assay determination of angiogenic factors . RESULTS Patient demographics were comparable . For all patients undergoing major lung resection , postoperative Ang-1 and sVEGFR2 levels were significantly decreased , while Ang-2 and sVEGFR1 levels markedly increased . No significant peri-operative changes in VEGF levels were observed . Compared with open group , VATS had significantly lower plasma levels of VEGF ( VATS 170 ± 93 pg/mL ; Open 486 ± 641 pg/mL ; P = 0.04 ) and Ang-2 ( VATS 2484 ± 1119 pg/mL ; Open 3379 ± 1287 pg/mL ; P = 0.026 ) on POD3 . CONCLUSIONS Major lung resection for early stage NSCLC leads to a pro-angiogenic status , with increased Ang-2 and decreased Ang-1 productions . VATS is associated with an attenuated angiogenic response with lower circulating VEGF and Ang-2 levels compared with open . Such differences in angiogenic factors may be important in lung cancer biology and recurrence following surgery . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot233

***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 vaccines based on human tumor-associated antigens ( TAA ) have been tested in patients with advanced or recurrent cancer , in combination with or following standard therapy . Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient's immune system . In animal models of human cancer , vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression . We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions ( advanced colonic adenomas , precursors to colon cancer ) , a vaccine based on the TAA MUC1 was highly immunogenic in 17 of 39 ( 43.6% ) of vaccinated individuals , eliciting high levels of anti-MUC1 immunoglobulin G ( IgG ) and long-lasting immune memory . Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells ( MDSC ) prevaccination . Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity . Our study shows that vaccines based on human TAAs are immunogenic and safe and capable of eliciting long-term memory that is important for cancer prevention . We also show that in the premalignant setting , immunosuppressive environment ( e.g. , high levels of MDSC ) might already exist in some individuals , suggesting an even earlier premalignant stage or preselection of nonimmunosuppressed patients for prophylactic vaccination . Cancer Prev Res ; 6(1) ; 18-26. �2012 AACR . OUTPUT: avoiding immune destruction INPUT: Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells ( Treg ) and plasmacytoid dendritic cells ( pDC ) that facilitate immune escape and correlate with poor prognosis . Here , we report that inducible costimulatory molecule ( ICOS ) , a T cell costimulatory molecule of the CTLA4/PD1/CD28 family , is expressed mostly by tumor-associated Treg in primary breast tumors . A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC . Indeed , tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal . In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells , establishing a pivotal role for ICOS in this process . Supporting these findings , the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis . Together , our results highlight an important relationship between Treg and pDC in breast tumors , and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells . These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer . Cancer Res ; 72(23) ; 6130-41. �2012 AACR . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot234

***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: Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia . Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells , it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors . More than a metabolic waste , the lactate anion is known to participate to cancer aggressiveness , in part through activation of the hypoxia-inducible factor-1 ( HIF-1 ) pathway in tumor cells . Whether lactate may also directly favor HIF-1 activation in endothelial cells ( ECs ) thereby offering a new druggable option to block angiogenesis is however an unanswered question . In this study , we therefore focused on the role in ECs of monocarboxylate transporter 1 ( MCT1 ) that we previously identified to be the main facilitator of lactate uptake in cancer cells . We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis . Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 ( VEGFR2 ) and basic fibroblast growth factor ( bFGF ) expression . Furthermore , using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry , we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects . Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells , the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities . OUTPUT: inducing angiogenesis INPUT: In patients with advanced bladder cancer , glucocorticoids are frequently given to reduce acute toxicity , particularly hyperemesis , during chemotherapy , as well as to improve cachectic conditions . However , it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor pathway . Glucocorticoid receptor expression was first investigated in human bladder cancer lines and tissue microarrays . Then , the effects of dexamethasone on glucocorticoid receptor transcription , cell proliferation , apoptosis/cell cycle , and invasion were examined in bladder cancer lines . Finally , mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression . All the cell lines and tissues examined were found to express glucocorticoid receptor . Dexamethasone increased glucocorticoid receptor-mediated reporter activity and cell proliferation , and inhibited apoptosis in the presence or absence of cisplatin . In contrast , dexamethasone suppressed cell invasion , the expression of its related genes [ MMP-2/MMP-9 , interleukin ( IL)-6 , VEGF ] , and the activity of MMP-2/MMP-9 , and also induced mesenchymal-to-epithelial transition . In addition , dexamethasone increased IκBα protein levels and cytosolic accumulation of NF-κB . In xenograft-bearing mice , dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites , suggestive of peritoneal dissemination of tumor cells , and actual metastasis . In all these assays , dexamethasone effects were abolished by a glucocorticoid receptor antagonist or glucocorticoid receptor knockdown via RNA interference . Thus , glucocorticoid receptor activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis . These results may provide a basis of developing improved chemotherapy regimens , including or excluding glucocorticoid receptor agonists/antagonists , for urothelial carcinoma . OUTPUT:

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

HoC_dynamic_1_shot235

***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: Furan , a potent rodent liver carcinogen , is found in many cooked food items and thus represents a human cancer risk . Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays , combined with analysis of histopathological and gene expression changes . In addition , formamidopyrimidine DNA glycosylase ( Fpg ) and endonuclease III ( EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage . Rats were treated by gavage on four consecutive days with 2 , 4 , and 8mg/kg bw furan , doses that were tumorigenic in 2-year cancer bioassays , and with two higher doses , 12 and 16mg/kg . Rats were killed 3h after the last dose , a time established as producing maximum levels of DNA damage in livers of furan-treated rats . Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion , with statistically significant increases detected at cancer bioassay doses . No DNA damage was detected in bone marrow , a non-target tissue for cancer , and peripheral blood micronucleus assays were negative . Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation , single-cell necrosis , apoptosis , and cell proliferation . In addition , genes related to apoptosis , cell-cycle checkpoints , and DNA-repair were expressed at a slightly lower level in the furan-treated livers . Although a mixed mode of action involving direct DNA binding cannot be ruled out , the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress , accompanied by inflammation , cell proliferation , and toxicity . OUTPUT: genomic instability and mutation;resisting cell death;tumor promoting inflammation;evading growth suppressors INPUT: The goal of the present study was to examine hepatic differential gene expression patterns in Fisher-344 rats in response to dietary 2-aminoanthracene ( 2AA ) ingestion for 14 and 28 days . Twenty four post-weaning 3-4 week old F-344 male rats were exposed to 0 mgkg(-1)-diet ( control ) , 50 mgkg(-1)-diet ( low dose ) , 75 mgkg(-1)-diet ( medium dose ) and 100 mgkg(-1)-diet ( high dose ) 2AA for 14 and 28 days . This was followed by analysis of the liver for global gene expression changes . In both time points , the numbers of genes affected seem to correlate with the dose of 2AA . Sixteen mRNAs were differentially expressed in all treatment groups for the short-term exposure group . Similarly , 51 genes were commonly expressed in all 28-day exposure group . Almost all the genes seem to have higher expression relative to the controls . In contrast , cytochrome P450 family 4 , subfamily a , polypeptide 8 ( Cyp4a8 ) , and monocyte to macrophage differentiation-associated ( Mmd2 ) were down-regulated relative to controls . Differentially expressed mRNAs were further analyzed for associations via DAVID . GO categories show the effect of 2AA to be linked with genes responsible for carbohydrate utilization and transport , lipid metabolic processes , stress responses such as inflammation and apoptosis processes , immune system response , DNA damage response , cancer processes and circadian rhythm . The data from the current study identified altered hepatic gene expression profiles that may be associated with carcinoma , autoimmune response , and/or type 2 diabetes . Possible biomarkers due to 2AA toxicity in the liver for future study include Abcb1a , Nhej1 , Adam8 , Cdkn1a , Mgmt , and Nrcam . OUTPUT:

genomic instability and mutation;resisting cell death;tumor promoting inflammation

HoC_dynamic_1_shot236

***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: "Many tumors contain heterogeneous populations of cells , only some of which exhibit increased tumorigenicity and resistance to anticancer therapies . Evidence suggests that these aggressive cancer cells , often termed "" cancer stem cells "" or "" cancer stem-like cells "" ( CSCs ) , rely upon developmental signaling pathways that are important for survival and expansion of normal stem cells . Here we report that , in analogy to embryonic mammary epithelial biology , estrogen signaling expands the pool of functional breast CSCs through a paracrine FGF/FGFR/Tbx3 signaling pathway . Estrogen or FGF9 pretreatment induced CSC properties of breast cancer cell lines and freshly isolated breast cancer cells , whereas cotreatment of cells with tamoxifen or a small molecule inhibitor of FGFR signaling was sufficient to prevent the estrogen-induced expansion of CSCs . Furthermore , reduction of FGFR or Tbx3 gene expression was able to abrogate tumorsphere formation , whereas ectopic Tbx3 expression increased tumor seeding potential by 100-fold . These findings demonstrate that breast CSCs are stimulated by estrogen through a signaling pathway that similarly controls normal mammary epithelial stem cell biology ." OUTPUT: sustaining proliferative signaling INPUT: "Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population . Several factors contribute to this increased frequency , including consanguineous marriages and an event known as a "" bottleneck "" , which occurred in the past and caused a drastic reduction in the genetic variability of this population . Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer . The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 ( 185delAG and 5382insC ) and BRCA2 ( 6174delT ) genes in an Ashkenazi Jewish population from Porto Alegre , Brazil . Molecular analyses were done by PCR followed by RFLP ( ACRS ) . The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively , and 0.4 for the BRCA2 6174deT mutation . These findings are similar to those of some prior studies but differ from others , possibly due to excluding individuals with a personal or family history of cancer . Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer . Furthermore , increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture . It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations ." OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot237

***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: Verbascum thapsus commonly known as ' mullein ' is part of a large family of Scrophulariaceae consisting of more than 360 species . From antiquity Verbascum thapsus has been used as a medicinal herb , it contains diverse polysaccharides , iroid glycosides , flavonoids , saponins , volatile oils and phenylentanoids . Inducible nitric oxide synthase ( iNOS ) represents one of the three isoforms that produce nitric oxide using L-arginine as a substrate in response to an increase in superoxide anion activated by NF-kB . It is implicated in different pathophysiological events and its expression increases greatly during an inflammatory process , due to oxidative stress and the activation of the enzymes of the antioxidant network such as SOD , CAT and GPx.In this study an inflammatory state was reproduced by treating THP-1 cells ( human myelomonocytic leukaemia ) with pro-inflammatory stimuli , such as LPS and IFN-gamma , obtaining an up-regulation both in the expression and in the activity of iNOS . The aim of the work was to investigate the antiinflammatory action of verbascoside using a concentration of 100 mum . The results show a significant decrease of the expression and activity of iNOS , extracellular O(2) ( - ) production , SOD , CAT and GPx activity when the cells were treated with verbascoside . Based on these results it is hypothesized that verbascoside has antiinflammatory properties since it reduces the production of superoxide radicals and consequently reduces the activity of iNOS . OUTPUT: tumor promoting inflammation INPUT: Vasohibin-1 ( VASH1 ) is isolated as an endothelial cell ( EC)-produced angiogenesis inhibitor . We questioned whether VASH1 plays any role besides angiogenesis inhibition , knocked-down or overexpressed VASH1 in ECs , and examined the changes of EC property . Knock-down of VASH1 induced premature senescence of ECs , and those ECs were easily killed by cellular stresses . In contrast , overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses . The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation . We sought to define the underlying mechanism . VASH1 increased the expression of ( superoxide dismutase 2 ) SOD2 , an enzyme known to quench reactive oxygen species ( ROS ) . Simultaneously , VASH1 augmented the synthesis of sirtuin 1 ( SIRT1 ) , an anti-aging protein , which improved stress tolerance . Paraquat generates ROS and causes organ damage when administered in vivo . More VASH1 ( +/- ) mice died due to acute lung injury caused by paraquat . Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat . Thus , VASH1 is a critical factor that improves the stress tolerance of ECs via the induction of SOD2 and SIRT1 . OUTPUT:

tumor promoting inflammation

HoC_dynamic_1_shot238

***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: Pam3CSK4 , a synthetic TLR2 ligand , has been shown to expand CD4+ regulatory T cells ( Treg cells ) . Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy ( IT ) . This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population . PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times : before IT and 6 mo and 1 y after the maximum-tolerated dose . This study was performed without a placebo-controlled group . D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production . Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition . TUNEL revealed that CD8+CD25+ Treg cells , but not CD4+CD25+ Treg cells , directly induced CD4+CD45ROhi+ apoptosis . Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells ; therefore , it may be a good adjuvant for the treatment of mite allergies . OUTPUT: evading growth suppressors;resisting cell death INPUT: There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of Tcell subsets in the local tumor environment reflects clinical outcome . Tumor infiltration by CD8(+) Tcells and regulatory Tcells ( Treg ) is associated with improved and reduced survival , respectively , in many cancer types . However , little is known of the prognostic value of immunological parameters measured in peripheral blood . In this study , peripheral CD8(+) T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival . Patients had a higher proportion of peripheral Treg , proliferating CD8(+) Tcells and CD8(+) Tcells with an activated effector phenotype compared with age-matched healthy controls . Higher proportions of Treg and proliferating CD8(+) Tcells were both associated with poor survival in univariate analyses ( hazard ratio [ HR ] 3.81 , 95% CI 1.69-8.57 ; p<0.01 and HR 2.86 , 95% CI 1.26-6.50 ; p<0.05 , respectively ) . CD8(+) Tcell proliferation was independently predictive of reduced survival in multivariate analysis ( HR 2.58 , 95% CI 1.01-6.61 ; p<0.05 ) . These findings suggest that peripheral CD8(+) T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot239

***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: UNLABELLED Oxygen free radicals and their reactive derivatives participate in formation of chronic inflammation states , which facilitate development of gastrointestinal tract tumors . Oxidative stress is one of the main causes of damage to cell membranes in result of exacerbated lipid peroxidation process . End products of lipid peroxidation ( aldehydes , organic peroxides ) react with important biological macromolecules such as DNA and proteins , cause changes in cell membrane structure and properties leading to loss of its integrity . Intensification of the lipid peroxidation process is a factor which may also lead to a malfunction in the antioxidant barrier , which further weakens the defense of cells against oxygen free radicals and promotes the onset and development of cancer . The aim of the study was the determination of lipid peroxidation level in gastrointestinal tract tumors ( stomach , liver , colon , and colorectal cancer to liver metastases ) . MATERIAL AND METHODS Materials for studies were obtained from 150 patients with gastrointestinal tract tumors : 10 with stomach cancer , 30 with malignant and benign liver cancers , 60 with primary colorectal cancer , and 50 with metachronous colorectal cancer liver metastases . We also investigated 25 patients with liver cirrhosis , which was treated as a pre-cancerous condition . In total , 175 patients were examined . Tumor specimens , and normal adjacent tissues ( 6-7 cm from the edge of the tumor ) , which served as control tissue in studies , were collected from patients ( with their consent ) during surgery . Additionally , liver specimens were collected from patients with liver cirrhosis . Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products , which in reaction with tiobarbituric acid ( TBA ) form colour complex ( thiobarbituric acid-reactive substances - TBARS ) . RESULTS The study showed the highest concentration of TBARS in benign , and the lowest in malignant liver tumors . Other types of gastrointestinal tumors studied , were characterized by similar levels of lipid peroxidation . TBARS concentration in these tumors was approximately 2-fold higher than in malignant liver tumors and much lower than in benign tumors . In all cancers of the digestive tract with the exception of malignant liver tumors increased level of TBARS was found , comparing with control tissue . The concentration of TBARS in cirrhotic liver was lower than in control . The level of lipid peroxidation in liver cirrhosis and malignant liver tumors was similar . There were no significant differences in TBARS concentration in the tumors of particular sections of the intestine and normal colon . The highest concentration of TBARS was found in G1 grade of colorectal cancer . In subsequent grades of cells differentiation ( G2 and G3 ) its concentration was lower . The highest level of lipid peroxidation , expressed as the concentration of TBARS was found in the I stage of colorectal cancer clinical advancement . The significantly lowest concentration of TBARS was shown for stage II ( UICC ) . CONCLUSIONS The level of lipid peroxidation in cancerous cells of gastrointestinal tract indicates increased oxidative stress . The changes of lipid peroxidation level--a marker of oxidative stress in gastrointestinal tumors appear to be closely associated with their development stages ( liver cirrhosis/malignant liver cancer ; colorectal cancer/colorectal cancer liver metastases ) and are likely to create such conditions , in which cancerous cells may proliferate , undergo gradual dedifferentiation and malignancy , and generate metastases . OUTPUT: tumor promoting inflammation INPUT: Liver metastasis from colorectal cancer is a leading cause of cancer mortality . Myeloid cells play pivotal roles in the metastatic process , but their prometastatic functions in liver metastasis remain incompletely understood . To investigate their role , we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells . Among the heterogeneous myeloid infiltrate , we identified a distinct population of CD11b/Gr1(mid) cells different from other myeloid populations previously associated with liver metastasis . These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2 . Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets . Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1(mid) recruitment and decreased tumor burden . Depletion of the CD11b/Gr1(mid) subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation . There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1(mid) cells . Additionally , an analogous myeloid subset was found in liver metastases of some colorectal cancer patients . Conclusion : Collectively , our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1(mid) subset-in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy . ( HEPATOLOGY 2012 ) . OUTPUT:

activating invasion and metastasis;avoiding immune destruction

HoC_dynamic_1_shot240

***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 soluble hexavalent chromium Cr ( VI ) used in industrial welding is an environmental contaminant widely recognized to act as a carcinogen , mutagen and teratogen towards humans and animals . The carcinogenic potential of metals is a major issue in defining human health risk from exposure . In the present investigation , 93 welders and 60 control subjects with similar mean ages , smoking prevalences and alcohol consumption were enrolled for DNA damage analysis in blood leucocytes by Micronucleus assay ( MN ) and the Comet assay . DNA repair inhibition was also analyzed by assessing XPD gene polymorphism . Welders showed a significant increase in micronucleated cells compared to controls with respect to their smoking habits and alcohol consumption , age and years of exposure ( P<0.05 ) . Results indicated that the welders had a larger mean comet tail length than that of the controls ( P<0.05 ) . The current study suggested that chronic occupational exposure to Cr ( VI ) during welding could lead to increased levels of DNA damage and repair inhibition . OUTPUT: genomic instability and mutation INPUT: BACKGROUND Acrylamide is a common dietary exposure that crosses the human placenta . It is classified as a probable human carcinogen , and developmental toxicity has been observed in rodents . OBJECTIVES We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother-child study . METHODS Hemoglobin ( Hb ) adducts of acrylamide and its metabolite glycidamide were measured in cord blood ( reflecting cumulated exposure in the last months of pregnancy ) from 1,101 singleton pregnant women recruited in Denmark , England , Greece , Norway , and Spain during 2006-2010 . Maternal diet was estimated through food-frequency questionnaires . RESULTS Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference . The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g ( 95% CI : -207 , -56 ) ; the corresponding difference for head circumference was -0.33 cm ( 95% CI : -0.61 , -0.06 ) . Findings were similar in infants of nonsmokers , were consistent across countries , and remained after adjustment for factors associated with reduced birth weight . Maternal consumption of foods rich in acrylamide , such as fried potatoes , was associated with cord blood acrylamide adduct levels and with reduced birth weight . CONCLUSIONS Dietary exposure to acrylamide was associated with reduced birth weight and head circumference . Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero . If confirmed , these findings suggest that dietary intake of acrylamide should be reduced among pregnant women . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot241

***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 typically display altered glucose metabolism characterized by a preference of aerobic glycolysis , known as the Warburg effect , which facilitates cell proliferation . Hypoxia-inducible factor ( HIF ) and oncoprotein Myc are two prominent transcription factors that drive glycolysis . Previously , we reported that the estrogen-related receptors ( ERRs ) act as cofactors of HIF and enhance HIF-dependent transcription of glycolytic genes under hypoxia . ERRs are orphan nuclear receptors and key regulators of energy metabolism by orchestrating mitochondrial biogenesis , fatty acid oxidation ( FAO ) and oxidative phosphorylation . Here , we show that ERRs also stimulate glycolysis under normoxia . ERRs directly bind to and activate promoters of many genes encoding glycolytic enzymes , and the ERR-binding sites in such promoters are essential for ERR-mediated transcriptional activation . ERRs interact with Myc , and the two factors synergistically activate transcription of glycolytic genes . Furthermore , overexpression of ERRs increases glycolytic gene expression and lactate production . Conversely , depletion of ERRs in cancer cells reduces expression of glycolytic genes and glucose uptake , resulting in decreased aerobic glycolysis and cell growth . Taken together , these results suggest that ERRs are important transcriptional activators of the glycolytic pathway and contribute to the Warburg effect in cancer cells . OUTPUT: cellular energetics;sustaining proliferative signaling INPUT: In cancer , glucose uptake and glycolysis are increased regardless of the oxygen concentration in the cell , a phenomenon known as the Warburg effect . Several ( but not all ) glycolytic enzymes have been investigated as potential therapeutic targets for cancer treatment using RNAi . Here , four previously untargeted glycolytic enzymes , aldolase A , glyceraldehyde 3-phosphate dehydrogenase , triose phosphate isomerase , and enolase 1 , are targeted using RNAi in Ras-transformed NIH-3T3 cells . Of these enzymes , knockdown of aldolase causes the greatest effect , inhibiting cell proliferation by 90% . This defect is rescued by expression of exogenous aldolase . However , aldolase knockdown does not affect glycolytic flux or intracellular ATP concentration , indicating a non-metabolic cause for the cell proliferation defect . Furthermore , this defect could be rescued with an enzymatically dead aldolase variant that retains the known F-actin binding ability of aldolase . One possible model for how aldolase knockdown may inhibit transformed cell proliferation is through its disruption of actin-cytoskeleton dynamics in cell division . Consistent with this hypothesis , aldolase knockdown cells show increased multinucleation . These results are compared with other studies targeting glycolytic enzymes with RNAi in the context of cancer cell proliferation and suggest that aldolase may be a useful target in the treatment of cancer . OUTPUT:

cellular energetics

HoC_dynamic_1_shot242

***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: Ovarian cancer-related angiogenesis is a complex process orchestrated by many positive and negative regulators . Many growth factors are involved in the development of the tumor-associated vasculature , and from these , endocrine gland-derived vascular endothelial growth factor ( EG-VEGF ) seems to play a crucial role . EG-VEGF is the first organ-specific angiogenic factor and its effects are restricted to the endothelial cells of the endocrine glands . Although EG-VEGF was detected in both normal and neoplastic ovaries , its clinical significance remains controversial . In the present study , we analyzed 30 patients with epithelial ovarian cancer , and the immunohistochemical expression of EG-VEGF was compared with the conventional clinico-pathological parameters of prognosis . Neoplastic cells of the ovarian carcinoma expressed EG-VEGF in 73.33% of the cases , as a cytoplasmic granular product of reaction . We found a strong correlation between the expression of EG-VEGF at protein level and tumor stage , grade , and microscopic type . The expression of EG-VEGF was found in patients with stage III and IV , but not in stage II . The majority of serous adenocarcinoma , half of the cases with clear cell carcinoma and two cases with endometrioid carcinoma showed definite expression in tumor cells . No positive reaction was found in the cases with mucinous carcinoma . Our results showed that EG-VEGF expression is an indicator not only of the advanced stage , but also of ovarian cancer progression . Based on these data , we concluded that EG-VEGF expression in tumor cells of the epithelial ovarian cancer is a good marker of unfavorable prognosis and could be an attractive therapeutic target in patients with advanced-stage tumors , refractory conventional chemotherapy . OUTPUT: inducing angiogenesis INPUT: Angiogenesis is a crucial step in the growth and metastasis of cancers , since it enables the growing tumor to receive oxygen and nutrients . Cancer prevention using natural products has become an integral part of cancer control . We studied the antiangiogenic activity of quercetin using ex vivo , in vivo and in vitro models . Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation , migration , invasion and tube formation of endothelial cells , which are key events in the process of angiogenesis . Most importantly , quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay ( CAM ) and matrigel plug assay . Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT , mTOR , and ribosomal protein S6 kinase in HUVECs . Quercetin ( 20 mg/kg/d ) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model , indicating that quercetin inhibited tumorigenesis by targeting angiogenesis . Furthermore , quercetin reduced the cell viability and induced apoptosis in prostate cancer cells , which were correlated with the downregulation of AKT , mTOR and P70S6K expressions . Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway , and could be used as a potential drug candidate for cancer therapy . OUTPUT:

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

HoC_dynamic_1_shot243

***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 Colorectal cancer is the third most common form of cancer in the industrial countries . Due to advances regarding the treatments , primarily development of improved surgical methods and the ability to make the earlier diagnosis , the mortality has remained constant during the past decades even though the incidence in fact has increased . To improve chemotherapy and enable personalised treatment , the need of biomarkers is of great significance . In this study , we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38 , the active metabolite of topoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis . MATERIAL AND METHODS The study included 3 colon cancer cell lines : KM12C , KM12SM and KM12l4a . The 3 cell lines were treated with SN-38 , and samples were obtained after 24 and 48 hour treatments . The gene expression analyses were performed using oligonucleotide microarrays comprising of approximately 27,000 spots where the untreated controls were compared to the SN-38-treated samples . RESULTS Unsupervised clustering clearly distinguished the treated cell lines from the untreated . Supervised analysis identified 3,974 significant genes ( p = 0.05 ) differentiating the treated samples from the untreated , majority of which were down-regulated after treatment . The top-ranked down-regulated genes in the treated cell lines included those related to receptor and kinase activity , signal transduction , apoptosis , RNA processing , protein metabolism and transport , cell cycle and transcription . A smaller number of genes were up-regulated in the cell lines after treatment and included genes involved in apoptosis , transcription , development and differentiation . CONCLUSIONS These results demonstrate that the expression of the genes involved in cell proliferation and apoptosis as well as RNA , DNA and protein metabolism were affected by SN-38 . The impact of certain genes on colorectal cancer development needs to be further evaluated ; however , these results could serve as a basis for further studies in order to find targets for irinotecan treatment . OUTPUT: evading growth suppressors;resisting cell death;sustaining proliferative signaling INPUT: INTRODUCTION Characterized by the development of hundreds to thousands of colonic adenomas , classic familial adenomatous polyposis ( FAP ) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer . Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However , there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 CASE PRESENTATION A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent , worsening , left lower quadrant abdominal pain . She had no family history of malignancy . Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon . Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa . Endoscopy revealed innumerable polyps . Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5 , resulting in a premature truncation of the APC protein at amino acid position 1312 . CONCLUSION Genetic information has only recently started being incorporated into clinical care . More research and randomized clinical trials need to be conducted to definitively characterize random mutations . Once these mutations are further understood , FAP patients may be able to be risk stratified and this may ultimately improve the screening , diagnosis , and treatment of this rare condition . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot244

***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: Food-derived heterocyclic aromatic amines ( HCAs ) have proved to be carcinogenic in both rodents and nonhuman primates . Two different metabolic pathways are suggested for the metabolic activation of HCA . The hepatic pathway proceeds via a two-step process involving N-hydroxylation by cytochrome P4501A2 and subsequent O-acetylation by N-acetyltransferase-2 . An alternative pathway may be of particular interest in extrahepatic tissues and proceeds via one-electron oxidation catalyzed by prostaglandin H synthase ( PHS ) , rendering free-radical metabolites . In this study , we investigated the metabolic activation of two HCAs , 2-amino-3-methylimidazo[4,5-f]quinoline ( IQ ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) , by two different enzyme systems in vitro , generating different primary and secondary reactive metabolites . Rat liver S9 mix and PHS were used as the activating system and represent the hepatic and extrahepatic pathways , respectively . Electron-spin resonance spectroscopy showed that both IQ and PhIP exerted inhibiting effects on PHS-mediated formation of hydroxyl radicals during the conversion of arachidonic acid to prostaglandins . Evidence for the formation of HCA free radicals was presented in an indirect way by the formation of glutathione-derived thiyl radicals , with purified PHS as the activating system . Activation by S9 mix did not result in the formation of detectable radical metabolites , showing that the two metabolic routes primarily led to the formation of different metabolites . In all electron-spin resonance experiments , IQ appeared to be more effective than PhIP . In contrasts , DNA adduct analysis by means of ( 32)P-postlabeling showed similar adduct patterns for S9 and PHS in single-stranded and double-stranded salmon testes DNA after incubation with PhIP , indicating the ultimate formation of a common reactive intermediate . For IQ , activation by PHS led to an additional adduct spot that was not present after S9 activation . Furthermore , activation of IQ resulted in higher adduct levels compared with PhIP for both activation pathways . Overall , adduct levels were higher in single-stranded DNA than double-stranded DNA . Our results showed that the hepatic and extrahepatic pathways resulted in different primary metabolites , while the ultimate formation of a similar reactive intermediate for PhIP , possibly an arylnitrenium ion , suggested that both pathways could play an important role in the onset of carcinogenesis . OUTPUT: genomic instability and mutation INPUT: The most potent tumorigen identified among the polycyclic aromatic hydrocarbons ( PAH ) is the nonplanar fjord region dibenzo[a,l]pyrene ( DB[a,l]P ) . It is metabolically activated in vivo through the widely studied diol epoxide ( DE ) pathway to form covalent adducts with DNA bases , predominantly guanine and adenine . The ( +)-11S,12R,13R,14S DE enantiomer forms adducts via its C14 position with the exocyclic amino group of guanine . Here , we present the first nuclear magnetic resonance solution structure of a DB[a,l]P-derived adduct , the 14R-(+)-trans-anti-DB[a,l]P-N(2)-dG ( DB[a,l]P-dG ) lesion in double-stranded DNA . In contrast to the stereochemically identical benzo[a]pyrene-derived N(2)-dG adduct ( B[a]P-dG ) in which the B[a]P rings reside in the B-DNA minor groove on the 3'-side of the modifed deoxyguanosine , in the DB[a,l]P-derived adduct the DB[a,l]P rings intercalate into the duplex on the 3'-side of the modified base from the sterically crowded minor groove . Watson-Crick base pairing of the modified guanine with the partner cytosine is broken , but these bases retain some stacking with the bulky DB[a,l]P ring system . This new theme in PAH DE-DNA adduct conformation differs from ( 1 ) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and ( 2 ) the base-displaced intercalation motif in which the damaged base and its partner are extruded from the helix . The structural considerations that lead to the intercalated conformation of the DB[a,l]P-dG lesion in contrast to the minor groove alignment of the B[a]P-dG adduct , and the implications of the DB[a,l]P-dG conformational motif for the recognition of such DNA lesions by the human nucleotide excision repair apparatus , are discussed . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot245

***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 Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat . Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients . Since constitutive activation of nuclear factor-κB ( NF-κB ) is necessary for tumour progression , NF-κB may be an important pharmacological target for this disease . Our study aimed to evaluate the antitumour effects of parthenolide , a NF-κB inhibitor , in two human glioblastoma cell lines ( U87MG and U373 ) and in glioblastoma xenografts . Furthermore , we aimed to investigate the molecular mechanisms underlying these effects . METHODS The anti-invasive and anti-angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays . Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT ( methyl thiazolyl tetrazolium ) assay . In addition , the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model . RESULTS We found that parthenolide suppresses proliferation , invasion , and tumour- induced angiogenesis of glioblastoma cells . Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors . Furthermore , parthenolide reduced Akt phosphorylation and activated mitochondrial signalling , suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-κB but also by the inhibition of Akt signalling and the activation of apoptotic proteins . Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts . CONCLUSION The present study identified parthenolide as a new therapeutic agent for glioblastomas . OUTPUT: activating invasion and metastasis;inducing angiogenesis;sustaining proliferative signaling;resisting cell death INPUT: Angiogenesis is the process of new blood vessel formation from pre-existing ones . Angiogenic factors contribute to neovascularization that takes place in angiogenesis-dependent diseases , including cancer . Inhibiting the activity of the angiogenic factors to block the angiogenesis pathways is the current strategy of cancer therapy . Basic fibroblast growth factor ( bFGF ) is regarded as one of the most important angiogenic factors . Herein , we selected polyoxometalates ( POMs ) with different structures to study the interactions between bFGF and POMs . The results show that POMs could bind to the protein with high affinity , causing detectable changes in conformation and biophysical properties of protein . In addition , POMs could effectively inhibit the cell proliferation induced by bFGF . Significantly , we found that the structure , size and composition of POMs play a key role in the interactions between bFGF and POMs . This study will be meaningful for future screening and design of polyoxometalate-based anticancer drugs . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot246

***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: Hepatocellular carcinoma ( HCC ) is one of the most common malignancies worldwide ; however , the prognosis of HCC patients remains poor . This poor prognosis is mainly attributed to the high rate of intrahepatic and distant metastasis . HCC often occurs in a hypoxic environment and hypoxia can activate metastatic programs , ultimately leading to tumor recurrence or metastasis . Thus , the discovery and subsequent development of novel agents to block HCC invasion and migration are the primary objectives of hepatic cancer research . The Notch1 signaling pathway might be involved in hypoxia-induced carcinoma metastasis . However , the mechanisms by which Notch1 mediates cell metastasis , particularly in hepatocellular carcinoma , are not yet entirely clear . The results of the present study show that hypoxia increases the invasion and migration capacities of different HCC cells . Activation of the Notch1 signaling pathway contributes to hypoxia-induced invasion and migration in HCC cells . The activated Notch1 signaling pathway can regulate Snail/E-cadherin through cyclooxygenase-2 ( COX-2 ) under hypoxic conditions . The above results suggest that the Notch1/COX-2/Snail/E-cadherin pathway is possibly associated with hypoxia-induced invasion and migration in HCC cells . Thus , targeting Notch1 may be useful for devising novel preventive and therapeutic strategies for HCC . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot247

***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: BACKGROUND/AIMS Analysis of cystic fluid may be useful in distinguishing between benign and malignant cysts which has significant impact on their management . The aim of our study was to assess the diagnostic utility of carcinoembryonic antigen ( CEA ) and K-ras gene mutation in pancreatic cysts fluid . METHODS The study included 56 patients with pancreatic cystic fluid collected for analysis . The cysts were classified as benign ( simple cysts , pseudocysts , serous cystadenoma ) - 39 patients or premalignant/malignant ( mucinous cystadenoma , IPMN , cystadenocarcinoma ) - 17 patients . The patients history , CEA fluid concentrations and presence of K-ras mutation were analyzed . RESULTS CEA were higher in patients with malignant cysts ( mean levels 238±12.5ng/ml ; range 32.8-4985ng/ml ) compared to benign lesions ( mean levels 34.5±3.7ng/ml ; range 3.9-693ng/ml ; p<0.001 ) . K-ras mutation correctly classified 11 of 17 patients with premalignant/malignant lesions . It was also detected in 1 patient with final diagnosis of benign cyst ( the sensitivity 64.7% and the specificity 97.4% ; p<0.01 ) . If CEA and molecular analysis were combined in that cysts with either CEA level>45ng/ml or presence of K-ras mutation , than 16 of 17 premalignant/malignant cysts were correctly identified ( 94.1% ) . CONCLUSION Molecular analysis of pancreatic cyst fluid adds diagnostic value to the preoperative diagnosis and should be considered when cyst cytologic examination is negative for malignancy . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot248

***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: Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies . Therefore , we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor ( ER)-negative breast epithelial cell line , MCF-10A . Cells were chronically exposed to a low-level arsenite ( 500nM ) for up to 24weeks . Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells ( SCs ) were examined . After 24weeks , chronic arsenic-exposed breast epithelial ( CABE ) cells showed increases in secreted MMP activity , colony formation , invasion , and proliferation rate , indicating an acquired cancer cell phenotype . These CABE cells presented with basal-like breast cancer characteristics , including ER-α , HER-2 , and progesterone receptor negativity , and overexpression of K5 and p63 . Putative CD44(+)/CD24(-/low) breast SCs were increased to 80% over control in CABE cells . CABE cells also formed multilayer cell mounds , indicative of loss of contact inhibition . These mounds showed high levels of K5 and p63 , indicating the potential presence of cancer stem cells ( CSCs ) . Epithelial-to-mesenchymal transition occurred during arsenic exposure . Overexpression of aromatase , a key rate-limiting enzyme in estrogen synthesis , occurred with arsenic starting early on in exposure . Levels of 17β-estradiol increased in CABE cells and their conditioned medium . The aromatase inhibitor letrozole abolished arsenic-induced increases in 17β-estradiol production and reversed cancer cell phenotype . Thus , chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs . Arsenic appears to transform breast epithelia through overexpression of aromatase , thereby activating oncogenic processes independent of ER . OUTPUT: activating invasion and metastasis;sustaining proliferative signaling;evading growth suppressors INPUT: Inorganic arsenic in the drinking water is a multisite human carcinogen that potentially targets the kidney . Recent evidence also indicates that developmental arsenic exposure impacts renal carcinogenesis in humans and mice . Emerging theory indicates that cancer may be a disease of stem cells ( SCs ) and that there are abundant active SCs during early life . Therefore , we hypothesized that inorganic arsenic targets SCs , or partially differentiated progenitor cells ( PCs ) , for oncogenic transformation . Thus , a rat kidney SC/PC cell line , RIMM-18 , was chronically exposed to low-level arsenite ( 500 nM ) for up to 28 weeks . Multiple markers of acquired cancer phenotype were assessed biweekly during arsenic exposure , including secreted matrix metalloproteinase ( MMP ) activity , proliferation rate , colony formation in soft agar , and cellular invasiveness . Arsenic exposure by 10 weeks and after also induced marked and sustained increases in colony formation , indicative of the loss of contact inhibition , and increased invasiveness , both cancer cell characteristics . Compared to the passage-matched control , chronic arsenic exposure caused exposure-duration dependent increases in secreted MMP-2 and MMP-9 activity , Cox-2 expression , and more rapid proliferation ( all >2-fold ) , characteristics typical of cancer cells . Dysregulation of SC maintenance genes and signaling pathways are common during oncogenesis . During arsenite exposure , expression of several genes associated with normal kidney development and SC regulation and differentiation ( i.e. , Wt-1 , Wnt-4 , Bmp-7 , etc. ) were aberrantly altered . Arsenic-exposed renal SCs produced more nonadherent spheroid bodies that grew much more aggressively in Matrigel , typical of cancer SCs ( CSCs ) . The transformed cells also showed gene overexpression typical of renal SCs/CSCs ( CD24 , Osr1 , Ncam ) and arsenic adaptation such as overexpression of Mt-1 , Mt2 , Sod-1 , and Abcc2 . These data suggest that inorganic arsenic induced an acquired cancer phenotype in vitro in these rat kidney SCs potentially forming CSCs and , consistent with data in vivo , indicate that these multipotent SCs may be targets of arsenic during renal carcinogenesis . OUTPUT:

activating invasion and metastasis;evading growth suppressors;sustaining proliferative signaling;tumor promoting inflammation

HoC_dynamic_1_shot249

***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 Angiogenesis represents a key element in the pathogenesis of malignancy . There are no robust data on prognostic factors for overall survival ( OS ) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor ( VEGF)-targeted therapy . The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer . METHODS Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers . Cox proportional hazards regression was used to identify independent prognostic factors for OS . RESULTS The median OS for the whole cohort was 19 months ( 95% CI , 14.3 to 23.6 months ) . Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology ( ASMO ) were independent predictors of short survival : serum lactate dehydrogenase ( LDH ) greater than the upper limit of normal ( ULN ; p<0.001 ) ; neutrophils greater than the ULN ( p<0.0014 ) ; and progression free survival ( PFS ) less than 6 months ( p =0.001 ) . CONCLUSION Serum LDH and neutrophil levels were the main prognostic factors in predicting survival , followed by PFS . This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents . OUTPUT: inducing angiogenesis INPUT: OBJECT A considerable body of evidence indicates that inflammation and angiogenesis play a significant role in the development and progression of chronic subdural hematoma ( CSDH ) . While various experimental and clinical studies have implicated placental growth factor ( PlGF ) in the processes that underpin pathological angiogenesis , no study has thus far investigated its expression in CSDH . The actions of PlGF and its related proangiogenic vascular endothelial growth factor ( VEGF ) are antagonized by a high-affinity soluble receptor , namely soluble VEGF receptor-1 ( sVEGFR-1 ) , and thus the ratio between sVEGFR-1 and angiogenic factors provides an index of angiogenic capacity . METHODS In the present study , using an automated electrochemiluminescence assay , levels of PlGF and sVEGFR-1 were quantified in serum and hematoma fluid obtained in 16 patients with CSDH . RESULTS Levels of PlGF and sVEGFR-1 were significantly higher in hematoma fluid than in serum ( p &lt ; 0.0001 ) . In serum , levels of sVEGFR-1 were higher than those of PlGF ( p &lt ; 0.0001 ) , whereas in hematoma fluid this difference was not apparent . Furthermore , the ratio of sVEGFR-1 to PlGF was significantly lower in hematoma fluid than in serum ( p &lt ; 0.0001 ) . CONCLUSIONS Given previous evidence indicating a role for PlGF in promoting angiogenesis , inflammatory cell chemotaxis , and stimulation , as well as its ability to amplify VEGF-driven signaling under conditions favoring pathological angiogenesis , enhanced expression of PlGF in hematoma fluid suggests the involvement of this factor in the mechanisms of inflammation and angiogenesis in CSDH . Furthermore , a reduced ratio of sVEGFR-1 to PlGF in hematoma fluid is consistent with the proangiogenic capacity of CSDH . Future studies are warranted to clarify the precise role of PlGF and sVEGFR-1 in CSDH . OUTPUT:

inducing angiogenesis;tumor promoting inflammation

HoC_dynamic_1_shot250

***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: Cellular senescence , an irreversible cell cycle arrest induced by a diversity of stimuli , has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy . Using a targeted proteomics approach , we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones , consistent with formation of senescence-associated heterochromatic foci . We also detected clear increases in repressive markers ( e.g. >50% elevation of H3K27me2/3 ) along with decreases in histone marks associated with increased transcriptional expression/elongation ( e.g . H3K36me2/3 ) . Despite the increases in repressive marks of chromatin , 179 loci ( of 2206 total ) were found to be upregulated by global quantitative proteomics . The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis . These alterations in primary metabolism are opposite to the well-known Warburg effect observed in cancer cells . This study significantly improves our understanding of stress-induced senescence and provides a potential application for triggering it in antiproliferative strategies that target the primary metabolism in cancer cells . OUTPUT: enabling replicative immortality;cellular energetics INPUT: Cellular senescence is a permanent out-of-cycle state regulated by molecular circuits acting during the G1 phase of the cell cycle . Cdt1 is a central regulator of DNA replication licensing acting during the G1 phase and it is negatively controlled by Geminin . Here , we characterize the cell cycle expression pattern of Cdt1 and Geminin during successive passages of primary fibroblasts and compare it to tumour-derived cell lines . Cdt1 and Geminin are strictly expressed in distinct subpopulations of young fibroblasts , similarly to cancer cells , with Geminin accumulating shortly after the onset of S phase . Cdt1 and Geminin are down-regulated when primary human and mouse fibroblasts undergo replicative or stress-induced senescence . RNAi-mediated Geminin knock-down in human cells enhances the appearance of phenotypic and molecular features of senescence . Mouse embryonic fibroblasts heterozygous for Geminin exhibit accelerated senescence compared to control fibroblasts . In contrast , ectopic expression of Geminin in mouse embryonic fibroblasts delays the appearance of the senescent phenotype . Taken together , our data suggest that changes in Geminin expression levels affect the establishment of senescence pathways . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot251

***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 polycomb group family protein BMI-1 is overexpressed by and functions as an oncogene in many different human cancers . We have previously shown that BMI-1 promotes the tumorigenicity of Ewing sarcoma family tumors ( ESFTs ) and that this is mediated independently of CDKN2A repression . In this study , we have discovered that high levels of BMI-1 confer resistance to contact inhibition in ESFT cells . Using stable retroviral transduction , we evaluated the consequences of BMI-1 knockdown on the growth of CDKN2A wild-type and mutant ESFT cells in subconfluent and confluent conditions . Although knockdown of BMI-1 had no effect on proliferation in low-density cultures , at high cell densities it resulted in cell cycle arrest and death . The normal cell contact inhibition response is mediated , in large part , by the recently described Hippo pathway which functions to inhibit cell proliferation and promote cell death by inactivating the Yes-Associated Protein ( YAP ) . Significantly , we found that YAP levels , activity and expression did not diminish in confluent ESFT cells that expressed high levels of BMI-1 . In contrast , YAP expression and nuclear localization were reduced in confluent BMI-1 knockdown cells suggesting that silencing of BMI-1 restored contact inhibition by restoring normal activation of the Hippo-YAP growth-suppressor pathway . Importantly , knockdown of YAP in ESFT cells resulted in profound inhibition of cell proliferation and anchorage-independent colony formation suggesting that stabilization and continued expression of YAP is critical for ESFT growth and tumorigenicity . Together , these studies reveal a previously unrecognized link between BMI-1 , contact inhibition and the Hippo-YAP pathway and suggest that resistance to contact inhibition in BMI-1 overexpressing cancer cells may be in part a result of Hippo inhibition and aberrant stabilization of YAP . OUTPUT: evading growth suppressors INPUT: Mps one binder 1a ( MOB1A ) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers . Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a(Δ/Δ)1b(tr/+) or Mob1a(Δ/+)1b(tr/tr) mice results in tumor development . Because most of these cancers resembled trichilemmal carcinomas , we generated double-mutant mice bearing tamoxifen-inducible , keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b ( kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation , apoptotic resistance , impaired contact inhibition , enhanced progenitor self renewal , and increased centrosomes . Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1 . Similarly , YAP1 was activated in some human trichilemmal carcinomas , and some of these also exhibited MOB1A/1B inactivation . Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis , and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway . OUTPUT:

evading growth suppressors;resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot252

***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: Chromosomal DNA must be in single-strand form for important transactions such as replication , transcription , and recombination to occur . The single-strand DNA ( ssDNA ) is more prone to damage than double-strand DNA ( dsDNA ) , due to greater exposure of chemically reactive moieties in the nitrogenous bases . Thus , there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA . To assess the potential hazard posed by such agents , we devised an ssDNA-specific mutagenesis reporter system in budding yeast . The reporter strains bear the cdc13-1 temperature-sensitive mutation , such that shifting to 37°C results in telomere uncapping and ensuing 5 ' to 3 ' enzymatic resection . This exposes the reporter region , containing three closely-spaced reporter genes , as a long 3 ' ssDNA overhang . We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase , APOBEC3G . APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand , resulting in frequent , simultaneous inactivation of two reporter genes . We then examined the mutagenicity of sulfites , a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake . Sulfites , at a concentration similar to that found in some foods , induced a high density of mutations , almost always as substitutions at cytosines in the ssDNA overhang strand , resulting in simultaneous inactivation of at least two reporter genes . Furthermore , sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil-DNA N-glycosylase . This intermediate was bypassed by error-prone translesion DNA synthesis , frequently involving Pol ζ , during repair synthesis . Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious , since cells might not possess the means to repair or bypass such lesions accurately . OUTPUT: genomic instability and mutation INPUT: Several germline single nucleotide polymorphisms ( SNPs ) have been identified in the POLB gene , but little is known about their cellular and biochemical impact . DNA Polymerase β ( Pol β ) , encoded by the POLB gene , is the main gap-filling polymerase involved in base excision repair ( BER ) , a pathway that protects the genome from the consequences of oxidative DNA damage . In this study we tested the hypothesis that expression of the POLB germline coding SNP ( rs3136797 ) in mammalian cells could induce a cancerous phenotype . Expression of this SNP in both human and mouse cells induced double-strand breaks , chromosomal aberrations , and cellular transformation . Following treatment with an alkylating agent , cells expressing this coding SNP accumulated BER intermediate substrates , including single-strand and double-strand breaks . The rs3136797 SNP encodes the P242R variant Pol β protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT , although P242R binds DNA similarly to WT . Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot253

***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 relevance of many BRCA2 variants of uncertain significance ( VUS ) to breast cancer has not been determined due to limited genetic information from families carrying these alterations . Here , we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain ( DBD ) missense mutations using a multifactorial likelihood model of cancer causality . Next , we evaluated the use of a homology-directed DNA break repair ( HDR ) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD . Compared with the known status of these variants based on the multifactorial likelihood model , the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [ 95% confidence interval ( CI ) : 75.3%-100% ] and specificity was estimated at 100% ( 95% CI : 81.5%-100% ) . A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results . When applied to 33 additional VUS , the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity . Thus , in the absence of genetic evidence , a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD , suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS . OUTPUT: genomic instability and mutation INPUT: Missense substitutions of uncertain clinical significance in the BRCA1 gene are a vexing problem in genetic counseling for women who have a family history of breast cancer . In this study , we evaluated the functions of 29 missense substitutions of BRCA1 in two DNA repair pathways . Repair of double-strand breaks by homology-directed recombination ( HDR ) had been previously analyzed for 16 of these BRCA1 variants , and 13 more variants were analyzed in this study . All 29 variants were also analyzed for function in double-strand break repair by the single-strand annealing ( SSA ) pathway . We found that among the pathogenic mutations in BRCA1 , all were defective for DNA repair by either pathway . The HDR assay was accurate because all pathogenic mutants were defective for HDR , and all nonpathogenic variants were fully functional for HDR . Repair by SSA accurately identified pathogenic mutants , but several nonpathogenic variants were scored as defective or partially defective . These results indicated that specific amino acid residues of the BRCA1 protein have different effects in the two related DNA repair pathways , and these results validate the HDR assay as highly correlative with BRCA1-associated breast cancer . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot254

***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: Metastasis is a major cause of death of patients with malignant tumors . Matrix metalloproteinases ( MMPs ) are important for the migration and invasion of various types of cancer cell . Propofol is a known anesthetic agent , widely used for short-term anesthesia and for longer-term sedation . Propofol inhibits the proliferation of a variety of tumor cells , but there is no available information regarding propofol-inhibited migration and invasion of tumor cells in vitro . In this study , we investigated the effects of propofol on the migration and invasion of human lung carcinoma A549 cells . Wound healing assay and Boyden chamber assays indicated that propofol inhibited the migration and invasion of A549 cells in vitro . Gelatin zymographic analysis showed the inhibitory effect of propofol on the activation of expression MMP-2 . Western blot analysis also indicated that propofol suppressed the protein expiration of growth factor receptor-bound protein 2 ( GRB2 ) , Jun N-terminal kinases 1/2 ( p-JNK1/2 ) , p-p38 , MMP-2 and MMP-9 in A549 cells . Results from real-time PCR assay also showed that propofol inhibited the mRNA gene expression of MMP-2 , -7 and -9 , and enhanced that of tissue inhibitor of metalloproteinase 1 ( TIMP1 ) and TIMP2 in A549 cells . Taken together , these data show that propofol inhibits MMP-2 and -9 mRNA and protein expressions , resulting in suppression of lung cancer cell invasion and migration in vitro . OUTPUT: activating invasion and metastasis INPUT: Breast cancer causes death due to distant metastases in which tumor cells produce matrix metalloproteinase ( MMP ) enzymes which facilitate invasion . Oleuropein , the main olive oil polyphenol , has anti-proliferative effects . This study aimed to investigate the effect of oleuropein on the metastatic and anti-metastatic gene expression in the MDA human breast cancer cell line . We evaluated the MMPs and TIMPs gene expression by semi-quantitative reverse transcriptase polymerase chain reaction ( RT-PCR ) in treated and untreated cells . This study demonstrated that OL may induce anti-metastatic effects on human breast cancer cells . We found that TIMP1,-3 , and -4 were over-expressed after all periods of incubation in treated cancer cells compared to untreated cells , while MMP2 and MMP9 genes were down-regulated , at least initially . Treatment of breast cancer cells with oleuropein could help in prevention of cancer metastasis by increasing the TIMPs and suppressing the MMPs gene expressions . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot255

***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 epidermal growth factor receptor ( EGFR ) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression . Panitumumab ( pmAb ) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions . In the present study , we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells ( HCT-8 , HT-29 , DLD-1 and HCT-116 ) . HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation ; HT-29 and HCT-8 exhibited an EGF-dependent proliferation , with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF . The effects of pmAb were then evaluated in the most EGF-responsive cells , HCT-8 . In that respect , pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase ( FAK ) as well as the EGF-induced invasive and migratory potential of colon cancer cells . At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors , such as membrane-type 1 metalloproteinase ( MT1-MMP ) , extracellular metalloproteinases inducer ( EMMPRIN ) , urokinase plasminogen activator ( uPA ) and syndecan-4 . The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation , resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth , migration and invasiveness as well as of matrix effector implicated in cancer progression . OUTPUT: sustaining proliferative signaling;activating invasion and metastasis INPUT: Invasion and metastasis are the major causes of cancer-related death . Pharmacological or therapeutic interventions such as chemoprevention of the progression stages of neoplastic development could result in substantial reduction in the incidence of cancer mortality . ( -)-Epigallocatechin-3-gallate ( EGCG ) , a promising chemopreventive agent , has attracted extensive interest for cancer therapy utilizing its antioxidant , anti- proliferative and inhibitory effects on angiogenesis and tumor cell invasion . In this study , we assessed the influence of EGCG on the proliferative potential of HeLa cells by cell viability assay and authenticated the results by nuclear morphological examination , DNA laddering assay and cell cycle analysis . Further we analyzed the anti-invasive properties of EGCG by wound migration assay and gene expression of MMP-9 and TIMP-1 in HeLa cells . Our results indicated that EGCG induced growth inhibition of HeLa cells in a dose- and time- dependent manner . It was observed that cell death mediated by EGCG was through apoptosis . Interestingly , EGCG effectively inhibited invasion and migration of HeLa cells and modulated the expression of related genes ( MMP-9 and TIMP-1 ) . These results indicate that EGCG may effectively suppress promotion and progression stages of cervical cancer development . OUTPUT:

resisting cell death;activating invasion and metastasis

HoC_dynamic_1_shot256

***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: The vacuolar H+-ATPase ( V-ATPase ) , a multisubunit proton pump , has come into focus as an attractive target in cancer invasion . However little is known about the role of V-ATPase in cell death and especially the underlying mechanisms remain mostly unknown . We used the myxobacterial macrolide archazolid B , a potent inhibitor of the V-ATPase , as an experimental drug as well as a chemical tool to decipher V-ATPase related cell death signaling . We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway . Prior to apoptosis induction archazolid lead to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1 alpha ( HIF1alpha ) and autophagy . Autophagy was induced at low concentrations of archazolid that do not alter pH in lysosomes and was shown by degradation of p62 or fusion of autophagosomes with lysosomes . HIF1alpha was induced due to energy stress shown by a decline of the ATP level and followed by a shut down of energy consuming processes . As silencing HIF1alpha increases apoptosis , the cellular stress response was suggested to be a survival mechanism . We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1alpha and finally leads to apoptosis . We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis , autophagy and cellular/metabolic stress . OUTPUT:

resisting cell death

HoC_dynamic_1_shot257

***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: Breast cancer is a heterogeneous disease at both the clinical and molecular levels . This heterogeneity may give rise to different therapy responses . Molecular profiling has facilitated identification of signatures for stratifying patients who would potentially benefit from given therapies . Previously , we reported on a subset of genes with the potential for predicting response of primary breast cancer to neoadjuvant chemotherapy . Herein , we report that patients with luminal ( estrogen receptor α [ ERα]-expressing ) breast cancer were enriched for nonresponders . To identify novel factors that contribute to the survival of breast cancer cells , a loss-of-function screen was performed with a subset of genes overexpressed in patients with disease resistant to chemotherapy . This approach led us to identify protein phosphatase 1 , regulatory subunit 15B ( PPP1R15B ) as a factor with a potentially essential role in the survival of ERα-positive breast cancer cells . Functional analyses showed that PPP1R15B depletion results in impaired proliferation due to unsuccessful transition of cells from G1 to S phase of the cell cycle , and apoptosis induction . Moreover , our data revealed a regulatory role for PPP1R15B in activating ERα . Furthermore , a high level of PPP1R15B mRNA expression was associated with poor outcome following tamoxifen-based therapy . Accordingly , knockdown of PPP1R15B expression sensitized tamoxifen-resistant MCF-7 breast cancer cells to tamoxifen while reducing ERα abundance in these cells . Our findings reveal a novel role for PPP1R15B in the survival and therapy response of ERα-positive breast cancer and may open new avenues for tumor subtype-specific therapeutic strategies in the era of personalized medicine . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot258

***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: Context:The ubiquitin-proteasome system and macroautophagy are two major pathways for intracellular protein degradation . Emerging lines of evidence have shown that blockade of ubiquitin-proteasome system by proteasome inhibitors activates macroautophagy.Objective:The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.Design:Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy , as well as LC3-II transition using Western blot . To ascertain the effect of Beclin 1 , cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1 . Cell viability and apoptotic cells were measured using MTT assay and flow cytometry , respectively.Results:Proteasome inhibitors decreased Beclin 1 expression . In addition , treatment with PI3K inhibitors 3-MA or wortmannin , as well as knockdown of Beclin 1 expression , was unable to affect autophagic responses mediated by proteasome inhibitors . Overexpression of Beclin 1 enhanced proteasome inhibitor-mediated cytotoxicity of thyroid cancer cells via suppression of survivin.Conclusions:Proteasome inhibitors cause Beclin 1-independent macroautophagic responses of thyroid cancer cells in a Beclin 1-independent manner . Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors . OUTPUT: resisting cell death INPUT: Benzyl isothiocyanate ( BITC ) is a dietary chemopreventive agent that inhibits the growth of various human cancer cells by causing apoptotic cell death . In this study , we demonstrate that BITC not only induces apoptosis but also induces autophagy in human hormone-sensitive ( Rv1 ) and -refractory ( PC3 ) prostate cancer cells . In BITC-treated cells , the induction of autophagy was detected by monitoring the processing of an autophagy marker protein , microtubule-associated protein 1 light chain 3 ( LC3 ) , the aggregation of LC3 into granular structures and the formation of acidic organelles . Inhibition of autophagy using 3-methyladenine increased BITC-induced apoptosis , whereas the administration of caspase inhibitor suppressed BITC-induced cell death . Our data also showed that BITC inhibits mammalian target of rapamycin ( mTOR ) kinase activity in a dose-dependent manner . The expression of phospho-mTOR ( Ser2481 ) , an indicator of mTOR intrinsic catalytic activity , and phospho-UNC-51-like kinase 1 ( Ser757 ) , a direct substrate of mTOR , were decreased in BITC-treated cells . However , the increased expression of phospho-mTOR ( Ser2448 ) , phospho-AKT ( Ser473 ) and antiapoptotic Bcl-2 were detected only in PC3 cells at later stages of BITC treatment . Collectively , our results show that BITC induces a protective autophagy response in Rv1 and PC3 cells through inhibition of the mTOR signaling pathway . Activation of the AKT survival pathway was only observed in PC3 cells , representing a resistance mechanism of advanced prostate cancer upon BITC treatment . These findings could potentially contribute to the beneficial effect of BITC in prostate cancer treatments . OUTPUT:

resisting cell death

HoC_dynamic_1_shot259

***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 Treatment decisions are difficult in clinically localised prostate cancer and further biomarkers of aggressive behaviour are required . We investigated the hypothesis that the tissue expression of three cell cycle markers , Rb , p21 and p16 , would provide helpful prognostic information in a well characterised series of prostate cancers which were clinically localised and treated conservatively . METHODS The immunohistochemical staining expression of these markers was assessed in tissue microarrays and correlated with 10 year prostate cancer survival and overall survival and then compared with pathological data including contemporary Gleason score , age , measures of tumour extent and initial serum prostate specific antigen ( PSA ) level . RESULTS Rb overexpression did not show any significant association with Gleason score or prostate cancer survival. p21 protein expression showed a significant association with prostate cancer survival ( p = 0.02 ) and overall survival ( p = 0.01 ) in a univariate model but not in a multivariate model with pathological and serum PSA data . There was a significant association between p16 cytoplasmic expression and prostate cancer survival ( HR = 2.52 , 95%CI = 1.79-3.55 , p < 0.001 ) and overall survival ( HR = 1.54 , 95% CI = 1.20-1.98 , p = 0.001 ) in a univariate model. p16 expression remained an independent prognostic factor for prostate cancer survival ( HR = 1.50 , 95%CI = 1.05-2.14 , p = 0.03 ) . CONCLUSION We conclude that p16 cytoplasmic expression can be used as a predictor of outcome in conservatively treated prostate cancer . Rb and p21 show no independent association with outcome and therefore further research is not warranted . OUTPUT: evading growth suppressors INPUT: OBJECTIVE To explore the clinical significance of miRNA-216a expression in pancreatic cancer . METHODS Fourteen patients with pancreatic cancer undergoing pancreaticoduodenectomy and 6 patients with benign pancreas lesions were examined for miR-216a expressions in the tumor or lesion tissues using Agilent Human miRNA Microarray ( V12.0 ) . The relationship between miR-216a expressions and the clinicopathological features of the patients was analyzed . RESULTS The expression of miRNA-216a was significantly lower in pancreatic cancer than in benign pancreas lesions ( P=0.000 ) . The expression of miRNA-216a was significantly correlated with the T stage of the tumor ( P=0.002 ) , but not with the patients ' age , gender , smoking status , tumor stage , lymph node metastases , distant metastasis , tumor differentiation , nerve invasion , vessel invasion or serum CA19-9 level ( P>0.05 ) . CONCLUSIONS The down-regulated expression of miR-216a in pancreatic cancer suggests the involvement of miR-216a in the tumorigenesis and development of pancreatic cancer. miR-216a may potentially serve as a novel tumor marker and also a prognostic factor for pancreatic cancer . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot260

***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: Food-derived heterocyclic aromatic amines ( HCAs ) have proved to be carcinogenic in both rodents and nonhuman primates . Two different metabolic pathways are suggested for the metabolic activation of HCA . The hepatic pathway proceeds via a two-step process involving N-hydroxylation by cytochrome P4501A2 and subsequent O-acetylation by N-acetyltransferase-2 . An alternative pathway may be of particular interest in extrahepatic tissues and proceeds via one-electron oxidation catalyzed by prostaglandin H synthase ( PHS ) , rendering free-radical metabolites . In this study , we investigated the metabolic activation of two HCAs , 2-amino-3-methylimidazo[4,5-f]quinoline ( IQ ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) , by two different enzyme systems in vitro , generating different primary and secondary reactive metabolites . Rat liver S9 mix and PHS were used as the activating system and represent the hepatic and extrahepatic pathways , respectively . Electron-spin resonance spectroscopy showed that both IQ and PhIP exerted inhibiting effects on PHS-mediated formation of hydroxyl radicals during the conversion of arachidonic acid to prostaglandins . Evidence for the formation of HCA free radicals was presented in an indirect way by the formation of glutathione-derived thiyl radicals , with purified PHS as the activating system . Activation by S9 mix did not result in the formation of detectable radical metabolites , showing that the two metabolic routes primarily led to the formation of different metabolites . In all electron-spin resonance experiments , IQ appeared to be more effective than PhIP . In contrasts , DNA adduct analysis by means of ( 32)P-postlabeling showed similar adduct patterns for S9 and PHS in single-stranded and double-stranded salmon testes DNA after incubation with PhIP , indicating the ultimate formation of a common reactive intermediate . For IQ , activation by PHS led to an additional adduct spot that was not present after S9 activation . Furthermore , activation of IQ resulted in higher adduct levels compared with PhIP for both activation pathways . Overall , adduct levels were higher in single-stranded DNA than double-stranded DNA . Our results showed that the hepatic and extrahepatic pathways resulted in different primary metabolites , while the ultimate formation of a similar reactive intermediate for PhIP , possibly an arylnitrenium ion , suggested that both pathways could play an important role in the onset of carcinogenesis . OUTPUT: genomic instability and mutation INPUT: Polycyclic aromatic hydrocarbons ( PAHs ) likely play a role in many cancers even in never-smokers . We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures , multiple genetic polymorphisms in genes related to metabolic and repair pathways , and nucleotide excision repair ( NER ) capacity . In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran , we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes . NER capacity was evaluated by a modified comet assay , and aromatic DNA adduct levels were measured in blood by32P-postlabeling . Multivariable regression models were compared by Akaike's information criterion ( AIC ) . Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides ( mean : 5.8 ± 3.1 ) . DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype , and was higher in the MPO homozygote risk-allele genotype . The sum of risk alleles in these genes significantly correlated with the log-adduct level ( r = 0.4 , p &lt ; 0.001 ) . Compared with the environmental model , adding Phase I SNPs and NER capacity provided the best fit , and could explain 17% more of the variation in adduct levels . NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes . Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies , with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot261

***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: Calcium ( Ca(2+) ) signals are involved in important checkpoints in cell death pathways and promote both apoptosis and autophagy . However , the relationship between autophagy and apoptosis in response to Ca(2+) level elevation is poorly understood . Here , we provided evidence that the influx of extracellular Ca(2+) triggered by Trichokonin VI ( TK VI ) , an antimicrobial peptide , induced calpain-dependent apoptosis and autophagy in hepatocellular carcinoma ( HCC ) cells . Remarkably , TK VI preferentially induced apoptosis that was associated with calpain-mediated Bax and Atg5 cleavage , which resulted in the collapse of the mitochondrial membrane potential and cytochrome c release . Interestingly , truncated , but not full-length Atg5 , associated with Bcl-xL and promoted the intrinsic pathway . Moreover , TK VI treatment induced reactive oxygen species ( ROS ) accumulation , an effect in which Bak might play a major role . This accumulation of ROS resulted in the subsequent disposal of damaged mitochondria within autophagosomes via Atg5-mediated and mitochondria-selective autophagy . Both the inhibition of calpain activity and Bax deficiency activated a switch that promoted an enhancement of autophagy . The inhibition of both apoptosis and autophagy significantly attenuated the TK VI cytotoxicity , indicating that the two processes had stimulatory effects during TK VI-meditated cell death . These results suggested that calpain , Bak and Atg5 were molecular links between autophagy and apoptosis and revealed novel aspects of the crosstalk between these two processes . The potential of TK VI is proposed as a promising anticancer agent for its well-characterized activity of Ca(2+) agonist and as a possible novel therapeutic strategy that acts on cancer cell mitochondria . OUTPUT: resisting cell death;tumor promoting inflammation INPUT: Arginine deprivation is a promising strategy for treating ASS-negative malignant tumors including melanoma . However , autophagy can potentially counteract the effectiveness of this treatment by acting as a pro-survival pathway . By combining tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL ) with arginine deprivation using ADI-PEG20 ( pegylated arginine deiminase ) , we achieved enhanced apoptosis and accelerated cell death in melanoma cell lines . This implies a switch from autophagy to apoptosis . In our current investigation , we found that TRAIL could induce the cleavage of two key autophagic proteins , Beclin-1 and Atg5 , in the combination treatment . Using specific inhibitors for individual caspases , we found that caspase-8 inhibitor could completely abolish the cleavage . Furthermore , caspase-8 inhibitor was able to fully reverse the enhanced cytotoxicity induced by TRAIL . Inhibitors for caspase-3 , 6 , 9 , and 10 were able to block the cleavage of these two autophagic proteins to some extent and correspondingly rescue cells from the cytotoxicity of the combination of TRAIL and arginine deprivation . In contrast , calpain inhibitor could not prevent the cleavage of either Beclin-1 or Atg5 , and was unable to prevent cell death . Overall , our data indicate that the cleavage of Beclin-1 and Atg5 by TRAIL-initiated caspase activation is one of the mechanisms that lead to the enhancement of the cytotoxicity in the combination treatment . OUTPUT:

resisting cell death

HoC_dynamic_1_shot262

***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: Blockage of the metastasis process remains a significant clinical challenge , requiring innovative therapeutic approaches . For this purpose , molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor , the tissue inhibitor of metalloproteinases ( TIMPs ) , are potentially interesting . In a previous study , we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L ( N6L ) for the most potent analog , inhibit both tumor growth and angiogenesis . Furthermore , they prevent metastasis in a RET transgenic mice model which develops melanoma . Here , we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells . Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model . This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix . This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP-3 . The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L . The inhibition of tumor cell invasion by N6L demonstrated in this study , in addition to its previously established inhibitory effect on tumor growth and angiogenesis , suggests that N6L represents a promising anticancer drug candidate warranting further investigation . OUTPUT: activating invasion and metastasis;inducing angiogenesis INPUT: Oncogene-induced senescence can provide a protective mechanism against tumour progression . However , production of cytokines and growth factors by senescent cells may contribute to tumour development . Thus , it is unclear whether induction of senescence represents a viable therapeutic approach . Here , using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients , we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis , induced senescence and markedly blocked proliferation in patient tumour implants . Importantly , when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment , 50% of the tumours did not progress over a 12-month period . Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response , which mediated senescence and a NF-κB-related , senescence-associated secretory phenotype ( SASP ) . Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP . Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth . Altogether , these data demonstrate that induction of senescence , coupled with immune surveillance , can limit melanoma growth . OUTPUT:

enabling replicative immortality;genomic instability and mutation

HoC_dynamic_1_shot263

***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: Dimethyl sulfoxide ( DMSO ) , a well-known differentiation inducer in several myeloid cells , also induces a reversible G(1) arrest in many cell lines . We recently showed that DMSO induces a G(1) phase arrest in Chinese hamster ovary ( CHO ) cells , by restoring contact inhibition and preventing high density-dependent apoptosis . CHO cells are frequently used in cell biology and mutagenesis studies due to their good growth capacity and ease of manipulation but are very difficult to synchronize by serum starvation since they detach from monolayers when they reach confluence . In this study we investigated the possibility of using DMSO to reversibly synchronize CHO cells in the G(1) phase of the cell cycle and analysed whether toxic effects follow the arrest using growth curve , sister chromatid exchange and micronuclei assays . We carried out a kinetic analysis of the arrest by DMSO and re-entry into the cell cycle after drug release by cytofluorimetric analysis of DNA content and bromodeoxyuridine incorporation . We show that CHO cells are efficiently and reversibly arrested in G(1) by DMSO in concentrations ranging between 1 and 2% . In our experiments , >90% of cells grown for 96 h in presence of the drug were arrested in G(1) and synchronously re-entered S phase approximately 8-12 h after release . Furthermore , expression levels of p27 were down-regulated during G(1) progression and cyclin D3 and E expression patterns were similar to those observed after serum starvation . No detectable cytotoxicity or genetic damage were induced in G(1) released cells as revealed by the tests employed . Our results show that DMSO is a very powerful inducer of G(1) synchronization in CHO cells without detectable cytotoxic or genetic effects in cell populations released from G(1) arrest . DMSO synchronization represents a model system in which to analyse protein activities regulating G(1) progression and investigate the response of G(1) cells to mutagen treatments . OUTPUT: sustaining proliferative signaling;evading growth suppressors;genomic instability and mutation INPUT: Identifying prognostic factors for osteosarcoma ( OS ) aids in the selection of patients who require more aggressive management . CD133 has been found to be a prognostic factor of certain tumor types . However , the association between CD133 expression and the prognosis of OS remains unknown . In this study , we analyzed the association of CD133 expression in OS with clinical factors and overall survival , and further investigated its potential role in metastasis in vitro . We found CD133 expression in 65.7% ( 46/70 ) of OS samples using immunohistochemistry , and it was positively correlated with lung metastasis analyzed by Chi-square test ( P=0.002 ) and shorter overall survival time using the Kaplan-Meier method compared by log-rank test ( P=0.000 ) . Multivariate analysis showed that CD133 expression was an independent prognostic factor of patients with OS . To test for direct participation of CD133 , we separated CD133(+) and CD133(-) cells in the MG63 cell line using magnetic-activated cell sorting and found that CD133(+) cells were more active in migration by scratch wound-healing assay and invasion by Matrigel invasion assay compared with CD133(-) cells . Elevated mRNA expression of the stemness gene octamer-binding transcription factor 4 ( Oct-4 ) and NANOG , and the metastasis-related receptor C-X-C chemokine receptor type 4 ( CXCR4 ) were also found in CD133(+) cells by reverse transcription-polymerase chain reaction . Thus , expression of CD133 was correlated with lung metastasis and poor prognosis in OS patients . CD133(+) cells may be a type of cancer stem cell with high expression of self-renewal capacity and metastasis-related genes . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot264

***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: Endoplasmic reticulum ( ER ) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear . We report here that eukaryotic elongation factor-2 kinase ( EEF2K ) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells . DDIT4 , a stress-induced protein , was required for transducing the signal for activation of EEF2K under ER stress . We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy , while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy . Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells . Moreover , inhibiting EEF2K by either RNAi or NH125 , a small molecule inhibitor of the enzyme , rendered tumor cells more sensitive to curcumin and velcade , two anticancer agents that possess ER stress-inducing action . Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress , and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response , thereby potentiating the efficacy of the ER stress-inducing agents against cancer . OUTPUT: resisting cell death INPUT: Ursolic acid ( UA ) is a pentacyclic triterpenoid with promising cancer chemopreventive properties . A better understanding of the mechanisms underlying anticancer activity of UA is needed for further development as a clinically useful chemopreventive agent . Here , we found that both endoplasmic reticulum ( ER ) stress and autophagy were induced by UA in MCF-7 human breast cancer cells . Surprisingly , ER stress was identified as an effect rather than a cause of UA-induced autophagy . Autophagy-dependent ER stress protected the cells from UA-induced apoptosis through EIF2AK3-mediated upregulation of MCL1 . Activation of MAPK1/3 but not inhibition of MTOR pathway contributed to UA-induced cytoprotective autophagy in MCF-7 cells . Our findings uncovered a novel cellular mechanism involved in the anticancer activity of UA , and also provided a useful model to study biological significance and mechanisms of autophagy-mediated ER stress . OUTPUT:

resisting cell death

HoC_dynamic_1_shot265

***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 development of targeted therapies and immunotherapies has markedly advanced the treatment of metastasized melanoma . While treatment with selective BRAF(V600E) inhibitors ( like vemurafenib or dabrafenib ) leads to high response rates but short response duration , CTLA-4 blocking therapies induce sustained responses , but only in a limited number of patients . The combination of these diametric treatment approaches may further improve survival , but pre-clinical data concerning this approach is limited . We investigated , using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice , whether BRAF(V600E) inhibition can synergize with anti-CTLA-4 mAb treatment , focusing on the interaction between the BRAF(V600E) inhibitor PLX4720 and the immune system . While PLX4720 treatment strongly decreased tumor growth , it did not induce cell death in BRAF(V600E)/PTEN(-/-) melanomas . More strikingly , PLX4720 treatment led to a decreased frequency of tumor-resident T cells , NK-cells , MDSCs and macrophages , which could not be restored by the addition of anti-CTLA-4 mAb . As this effect was not observed upon treatment of BRAF wild-type B16F10 tumors , we conclude that the decreased frequency of immune cells correlates to BRAF(V600E) inhibition in tumor cells and is not due to an off-target effect of PLX4720 on immune cells . Furthermore , anti-CTLA-4 mAb treatment of inducible melanoma mice treated with PLX4720 did not result in enhanced tumor control , while anti-CTLA-4 mAb treatment did improve the effect of tumor-vaccination in B16F10-inoculated mice . Our data suggest that vemurafenib may negatively affect the immune activity within the tumor . Therefore , the potential effect of targeted therapy on the tumor-microenvironment should be taken into consideration in the design of clinical trials combining targeted and immunotherapy . OUTPUT: avoiding immune destruction INPUT: Approximately 50% of melanomas require oncogenic B-RAF(V600E) signaling for proliferation , survival , and metastasis , and the use of highly selective B-RAF inhibitors has yielded remarkable , although short-term , clinical responses . Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors , and the identification of B-RAF targets may therefore provide new strategies for managing melanoma . In this report , we applied whole-genome expression analyses to reveal that oncogenic B-RAF(V600E) regulates genes associated with epithelial-mesenchymal transition in normal cutaneous human melanocytes . Most prominent was the B-RAF-mediated transcriptional repression of E-cadherin , a keratinocyte-melanoma adhesion molecule whose loss is intimately associated with melanoma invasion and metastasis . Here we identify a link between oncogenic B-RAF , the transcriptional repressor Tbx3 , and E-cadherin . We show that B-RAF(V600E) induces the expression of Tbx3 , which potently represses E-cadherin expression in melanocytes and melanoma cells . Tbx3 expression is normally restricted to developmental embryonic tissues and promoting cell motility , but it is also aberrantly increased in various cancers and has been linked to tumor cell invasion and metastasis . We propose that this B-RAF/Tbx3/E-cadherin pathway has a critical role in promoting the metastasis of B-RAF-mutant melanomas . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot266

***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: Cantharidin is an active constituent of mylabris , a traditional Chinese medicine . It is a potent and selective inhibitor of protein phosphatase 2A ( PP2A ) that plays an important role in control of cell cycle , apoptosis , and cell-fate determination . Owing to its antitumor activity , cantharidin has been frequently used in clinical practice . In the present study , we investigated the therapeutic potential of cantharidin in pancreatic cancer . Cantharidin efficiently inhibited the growth of pancreatic cancer cells , but presented a much lighter toxicity effect against normal pancreatic duct cells . It caused G2/M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 ( CDK1 ) and up-regulation of p21 expression . It induced apoptosis and elevated the expressions of pro-apoptotic factors tumor necrosis factor-alpha ( TNF-alpha ) , TNF-related apoptosis inducing receptor 1 ( TRAILR1 ) , TRAILR2 , Bad , Bak , and Bid , and decreased the expression of anti-apoptotic Bcl-2 . Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis . Interestingly , unlike previous studies on other cancer cells , we found that the inhibitory role of cantharidin is independent of oxidative stress in pancreatic cancer cells . Mitogen-activated protein kinases ( MAPKs ) , including ERK , JNK , and p38 , were activated after treatment with cantharidin . Inhibition of JNK , but not ERK or p38 , alleviated the cytotoxity effect of cantharidin , suggesting cantharidin exerted its anticancer effect through the JNK-dependent way . Hence , in addition to being an attractive candidate compound with therapeutic potential , cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment . OUTPUT: evading growth suppressors;resisting cell death;sustaining proliferative signaling INPUT: Phyllanthus urinaria is widely used as anti-inflammatory , antiviral , antibacterial , and anti-hepatotoxic medicines in almost every tropical country . However , scientific evidence supporting its use in cancer metastasis is limited , particularly osteosarcoma . We investigated the effect of P. urinaria extract ( PUE ) on cell viability , invasion , and migration in the human osteosarcoma Saos-2 cell line , and looked at the impact of PUE on several relevant proteases and signaling pathways . This study demonstrates that PUE , at a range of concentrations ( from 0 to 100 μg/ml ) , concentration-dependently inhibited the migration/invasion capacities of Saos-2 without cytotoxic effects . Zymographic and western blot analyses revealed that PUE inhibited the urokinase-type plasminogen activator ( u-PA ) and matrix metalloproteinase-2 ( MMP-2 ) enzyme activity , as well as protein expression . Western blot analysis also showed that PUE inhibits phosphorylation of ERK1/2 and Akt . Testing of mRNA level , quantitative real-time PCR , and promoter assays evaluated the inhibitory effects of PUE on u-PA expression in Saos-2 cells . The chromatin immunoprecipitation ( ChIP ) assay was reactive to the transcription protein SP-1 , which was inhibited by PUE . In conclusion , PUE suppresses human osteosarcoma Saos-2 cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways . Therefore , PUE produces anti-metastatic activity in Saos-2 cells . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot267

***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: Helicobacter hepaticus-infected Rag2(-/-) mice emulate many aspects of human inflammatory bowel disease , including the development of colitis and colon cancer . To elucidate mechanisms of inflammation-induced carcinogenesis , we undertook a comprehensive analysis of histopathology , molecular damage , and gene expression changes during disease progression in these mice . Infected mice developed severe colitis and hepatitis by 10wk post-infection , progressing into colon carcinoma by 20wk post-infection , with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages . Transcriptional profiling revealed decreased expression of DNA repair and oxidative stress response genes in colon , but not in liver . Mass spectrometric analysis revealed higher levels of DNA and RNA damage products in liver compared to colon and infection-induced increases in 5-chlorocytosine in DNA and RNA and hypoxanthine in DNA . Paradoxically , infection was associated with decreased levels of DNA etheno adducts . Levels of nucleic acid damage from the same chemical class were strongly correlated in both liver and colon . The results support a model of inflammation-mediated carcinogenesis involving infiltration of phagocytes and generation of reactive species that cause local molecular damage leading to cell dysfunction , mutation , and cell death . There are strong correlations among histopathology , phagocyte infiltration , and damage chemistry that suggest a major role for neutrophils in inflammation-associated cancer progression . Further , paradoxical changes in nucleic acid damage were observed in tissue- and chemistry-specific patterns . The results also reveal features of cell stress response that point to microbial pathophysiology and mechanisms of cell senescence as important mechanistic links to cancer . OUTPUT: tumor promoting inflammation;genomic instability and mutation;resisting cell death INPUT: Many molecular mechanisms contribute to the development of doxorubicin resistance and different cancers can express wide and diverse arrays of drug-resistance genes . The aim of this study was to identify the changes in gene expression associated with the development of doxorubicin resistance in MCF7 breast cancer cell line . The doxorubicin resistant MCF7 cell line was developed by stepwise selection of MCF7 cells and was tested using the MTT assay . The alterations in gene expression were examined using the real-time based PCR array . The findings showed an up-regulation of many phase I/II metabolizing genes , specifically , the CYP1A1 and the CYP1A2 that were up-regulated by 206- and 96-fold respectively . Drug efflux pump genes were also up-regulated profoundly . TOP2A was strongly down-regulated by 202-fold . Many other changes were observed in genes crucial for cell cycle , apoptosis and DNA repair . The findings of this project imply that the development of doxorubicin resistance is a multi-factorial process . OUTPUT:

genomic instability and mutation;resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot268

***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: Metastasis is the most lethal attribute of human malignancy . High-level expression of survivin is involved in both carcinogenesis and angiogenesis in cancer . Previous studies indicate that a mutation of the threonine residue at position 34 ( Thr34Ala ) of survivin generates a dominant-negative mutant that induces apoptosis , inhibits angiogenesis , and suppresses highly metastatic breast carcinoma in mouse models . We investigated the efficacy of gene therapy with a survivin dominant-negative mutant and possible factors related to lymph node metastasis . The metastasis rate was compared between each group in order to find a survivin-targeted therapy against lymphangiogenesis in its earliest stages . We established lymph node metastasis models and treated animals with H22 tumors with Lip-mSurvivinT34A ( Lip-mS ) , Lip-plasmid ( Lip-P ) , or normal saline ( NS ) . Eight days after the last dose , five randomly chosen mice from each group were sacrificed . We detected the apoptotic index , microvessel density ( MVD ) , lymphatic microvessel density ( LMVD ) , and the expression of VEGF-D with immunohistochemistry . After the remaining animals were sacrificed , we compared the tumor-infiltrated lymph nodes in each group . Administration of mSurvivinT34A plasmid complexed with cationic liposome ( DOTAP/chol ) resulted in the efficacious inhibition of tumor growth and lymph node metastasis within the mouse H22 tumor model . These responses were associated with tumor cell apoptosis , and angiogenesis and lymphangiogenesis inhibition . Our results suggested that Lip-mSurvivinT34A induced apoptosis and inhibited tumor angiogenesis and lymphangiogenesis , thus suppressing tumor growth and lymphatic metastasis . The mSurvivinT34A survivin mutant is a promising strategy of gene therapy to inhibit lymphatic metastasis . OUTPUT: activating invasion and metastasis;inducing angiogenesis;resisting cell death INPUT: AIM To investigate the role of delta-like ligand 4 ( DLL4 ) in the angiogenesis of high-grade malignant glioma . MATERIALS AND METHODS DLL4 expression and microvessel density ( MVD ) were detected by immunohistochemistry in 51 human high-grade malignant glioma tissue samples . The vessel maturation index ( VMI ) was calculated as the percentage of a-smooth muscle actin ( a-SMA)-positive vessels in relation to the amount of CD31-positive vessels . Double fluorescent immunostaining for CD31 and EphrinB2 or EphB4 was performed to identify the arterial ( EphrinB2 ) or venous ( EphB4 ) origins of glioma microvessels . RESULTS Strong immunostaining of DLL4 and a positive correlation of DLL4 with the MVD were observed in high-grade malignant gliomas . The VMI of the DLL4-positive group was significantly higher than that of the DLL4-negative group . However , no significant association was found between DLL4 and EphrinB2 or EphB4 in high-grade gliomas . CONCLUSION DLL4 may be an important regulator for vessel proliferation and maturation in human high-grade malignant gliomas . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot269

***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: Genetic and epigenetic changes in the von Hippel-Lindau ( VHL ) tumour suppressor gene are common in sporadic conventional ( clear cell ) renal cell carcinoma ( ccRCC ) . The effects on VHL expression are unknown but increased understanding may be relevant clinically , either in terms of prognosis or in therapy selection . We have examined the expression of VHL mutant RNA in 84 ccRCC tumours previously screened for mutations in genomic DNA , 56 of which contained 52 unique mutations or polymorphisms . Based on the predicted change to the primary amino acid sequence , 24 of the mutations were missense , 11 resulted in frameshifts with premature truncation , 9 resulted in immediate truncation at the site of the mutation and 2 were frameshifts which extended the reading frame beyond the normal stop codon . Nine tumours had intronic variants , including substitution of invariant residues at splice sites , deletion of nucleotides spanning the exon-intron junction , an intronic variant of unknown function and the polymorphism c.463+43A>G . Four variants were identified which were present in genomic DNA but not in mRNA . Three of these , all encoding apparent missense changes to the primary amino acid sequence , were located close to the ends of exons , reduced the strength of the splice site and function as null rather than missense variants . One nonsense variant was not detectable in mRNA but all other mutations resulting in premature truncation codons ( PTCs ) were , suggesting truncating VHL mutations may potentially generate truncated VHL protein . An intronic variant , c.341‑11T>A , previously regarded as of unknown function , is associated with an increased level of skipping of exon 2 and may , therefore , reduce production of pVHL . Our data show that the biological consequences of VHL mutations are not necessarily predictable from the sequence change of the mutation and that for the majority of VHL mutations , the potential for the generation of mutant protein exists . OUTPUT: genomic instability and mutation INPUT: Many viruses subvert the host cell's ability to mount and complete various DNA damage responses ( DDRs ) after infection . HCMV infection of permissive fibroblasts activates host DDRs at the time of viral deposition and during replication , but the DDRs remain uncompleted without arrest or apoptosis . We believe this was in part due to partitioning of the damage response and double strand break repair components . After extraction of soluble proteins , the localization of these components fell into three groups : specifically associated with the viral replication centers ( RCs ) , diffused throughout the nucleoplasm and excluded from the RCs . Others have shown that cells are incapable of processing exogenously introduced damage after infection . We hypothesized that the inability of the cells to process damage might be due to the differential association of repair components within the RCs and , in turn , potentially preferential repair of the viral genome and compromised repair of the host genome . To test this hypothesis we used multiple strategies to examine repair of UV-induced DNA damage in mock and virus-infected fibroblasts . Comet assays indicated that repair was initiated , but was not completed in infected cells . Quantitative analysis of immunofluorescent localization of cyclobutane pyrimidine dimers ( CPDs ) revealed that after 24 h of repair , CPDs were significantly reduced in viral DNA , but not significantly changed in the infected host DNA . To further quantitate CPD repair , we developed a novel dual-color Southern protocol allowing visualization of host and viral DNA simultaneously . Combining this Southern methodology with a CPD-specific T4 endonuclease V alkaline agarose assay to quantitate repair of adducts , we found efficient repair of CPDs from the viral DNA but not host cellular DNA . Our data confirm that NER functions in HCMV-infected cells and almost exclusively repairs the viral genome to the detriment of the host's genome . OUTPUT:

genomic instability and mutation

HoC_dynamic_1_shot270

***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: Calcium ( Ca(2+) ) signals are involved in important checkpoints in cell death pathways and promote both apoptosis and autophagy . However , the relationship between autophagy and apoptosis in response to Ca(2+) level elevation is poorly understood . Here , we provided evidence that the influx of extracellular Ca(2+) triggered by Trichokonin VI ( TK VI ) , an antimicrobial peptide , induced calpain-dependent apoptosis and autophagy in hepatocellular carcinoma ( HCC ) cells . Remarkably , TK VI preferentially induced apoptosis that was associated with calpain-mediated Bax and Atg5 cleavage , which resulted in the collapse of the mitochondrial membrane potential and cytochrome c release . Interestingly , truncated , but not full-length Atg5 , associated with Bcl-xL and promoted the intrinsic pathway . Moreover , TK VI treatment induced reactive oxygen species ( ROS ) accumulation , an effect in which Bak might play a major role . This accumulation of ROS resulted in the subsequent disposal of damaged mitochondria within autophagosomes via Atg5-mediated and mitochondria-selective autophagy . Both the inhibition of calpain activity and Bax deficiency activated a switch that promoted an enhancement of autophagy . The inhibition of both apoptosis and autophagy significantly attenuated the TK VI cytotoxicity , indicating that the two processes had stimulatory effects during TK VI-meditated cell death . These results suggested that calpain , Bak and Atg5 were molecular links between autophagy and apoptosis and revealed novel aspects of the crosstalk between these two processes . The potential of TK VI is proposed as a promising anticancer agent for its well-characterized activity of Ca(2+) agonist and as a possible novel therapeutic strategy that acts on cancer cell mitochondria . OUTPUT: resisting cell death;tumor promoting inflammation INPUT: K-Ras dependent non-small cell lung cancer ( NSCLC ) cells are ' addicted ' to basal autophagy that reprograms cellular metabolism in a lysosomal-sensitive manner . Here we demonstrate that the xenophagy-associated kinase TBK1 drives basal autophagy , consistent with its known requirement in K-Ras-dependent NSCLC proliferation . Furthermore , basal autophagy in this context is characterised by sequestration of the xenophagy cargo receptor Ndp52 and its paralogue Tax1bp1 , which we demonstrate here to be a bona fide cargo receptor . Autophagy of these cargo receptors promotes non-canonical NF-κB signalling . We propose that this TBK1-dependent mechanism for NF-κB signalling contributes to autophagy addiction in K-Ras driven NSCLC . OUTPUT:

resisting cell death

HoC_dynamic_1_shot271

***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: UVB from solar radiation is both an initiating and promoting agent for skin cancer . We have found that primary human keratinocytes undergo an apoptotic response to UVB . To determine whether these responses are altered during the course of immortalization , we examined markers of apoptosis in primary human foreskin keratinocytes ( HFK ) transduced with either a retroviral vector expressing the E6 and E7 genes of HPV-16 or with empty vector alone ( LXSN-HFK ) . Whereas LXSN-HFK as well as early passage keratinocytes expressing HPV-16 E6 and E7 ( p7 E6/7-HFK ) were both moderately responsive to UVB irradiation , late passage-immortalized keratinocytes ( p27 E6/7-HFK ) were exquisitely sensitive to UVB-induced apoptosis . After exposure to UVB , enhanced annexin V-positivity and internucleosomal DNA fragmentation were observed in p27 E6/7-HFK compared with either LXSN- or p7 E6/7-HFK . Caspase-3 fluorometric activity assays as well as immunoblot analysis with antibodies to caspase-3 and poly(ADP-ribose) polymerase revealed elevated caspase-3 activity and processing at lower UVB doses in p27 E6/7-HFK compared with LXSN- or p7 E6/7-HFK . In addition , the caspase inhibitor DEVD-CHO reduced the apoptotic response and increased survival of all three HFK types . Immunoblot analysis revealed that caspase-8 was activated in all three cell types , but caspase-9 was only activated in p27 E6/7-HFK . Cell cycle analysis further showed that only p27 E6/7-HFK exhibit G(2)/M accumulation that is enhanced by UVB treatment . This accumulation was associated with a rapid down-regulation of Bcl-2 in these cells . The immortalization process subsequent to the expression of HPV E6 and E7 may therefore determine UVB sensitivity by switching the mode of apoptosis from a caspase-8 to a Bcl-2-caspase-9-mediated pathway of apoptosis . OUTPUT: resisting cell death;enabling replicative immortality INPUT: Excessive exposure to solar UVA and UVB radiation is widely considered to cause skin cancers such as squamous cell carcinoma and basalioma . Direct UVB damage to skin cell DNA as well as UV-induced chronic skin inflammation , accelerated keratinocyte proliferation , inhibited apoptosis , and immunosuppression seem to underlie the UV-induced carcinogenesis . Also , UVB induces cytochrome P450 subfamilies ( CYP1A1 and CYP1B1 ) involved in metabolic activation of organic pro-carcinogens and their conversion to ultimate carcinogens . Here , the effects of several glycosylated and non-glycosylated plant polyphenols ( verbascoside , resveratrol , polydatin , rutin , and quercetin ) on the inflammatory , apoptotic , metabolic , and proliferative responses of cultured human epidermal keratinocytes ( HEK ) to non-cytotoxic doses of solar-simulated UVA+UVB and chemical mediators of UV signalling in HEK , 6-formylindolo[3,2-b]carbazole and squalene isolated from photo-oxidized skin surface lipids ( SSL ) , were evaluated . We showed that the stilbenes and quercetin being exposed to UV were photo-destroyed within a short period of time , while verbascoside and rutin were photo-stable . When SSL were exposed to UV , the stilbenes and quercetin remarkably accelerated photo-oxidation of alpha-tocopherol , squalene , and cholesterol fractions , whilst verbascoside protected them . Verbascoside invariably inhibited molecular pathways in HEK leading to inflammatory cytokine expression ( NFkappaB and EGFR/ERK phosphorylation ) , and cell proliferation ( EGFR nuclear translocation ) , and displayed a stimulus-specific effect on the metabolic axis aryl hydrocarbon receptor ( AhR)-CYP1A1/CYP1B1 . By contrast , the stilbenes inhibited UV-connected inflammatory cytokines excluding IL-8 , but they prevalently stimulated NFkappaB , EGFR nuclear translocation and the AhR-CYP pathway . We conclude that , among the PPs investigated , verbascoside does interfere with multiple UV-sensitive signalling in HEK in a way that it could have a major impact on skin cancer chemoprevention . OUTPUT:

sustaining proliferative signaling;tumor promoting inflammation

HoC_dynamic_1_shot272

***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: Reprogramming of cellular metabolism is a key eventduring tumorigenesis . Despite being known for decades ( Warburg effect ) , the molecular mechanisms regulating this switch remained unexplored . Here , we identify SIRT6 as a tumor suppressor thatregulates aerobic glycolysis in cancer cells . Importantly , loss of SIRT6 leads to tumor formation without activation of known oncogenes , whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth , suggesting that SIRT6 plays a role in both establishment and maintenance of cancer . By using a conditional SIRT6 allele , we show that SIRT6 deletion invivo increases the number , size , and aggressiveness of tumors . SIRT6 also functions as a regulator of ribosome metabolismby corepressing MYC transcriptional activity . Lastly,Sirt6 is selectively downregulated in several human cancers , and expression levels of SIRT6 predict prognosis and tumor-free survival rates , highlighting SIRT6 as a critical modulator of cancermetabolism . Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism . OUTPUT:

cellular energetics;genomic instability and mutation

HoC_dynamic_1_shot273

***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: The mechanisms by which hematopoietic stem and progenitor cells ( HSC and HPC ) from myelodysplastic syndromes ( MDS ) undergo ineffective production of blood cells and disease transformation into acute myeloid leukemia remain to be investigated . It has been confirmed that increased production of reactive oxygen species ( ROS ) under various pathological conditions impairs HSC self-renewal and causes HSC premature exhaustion and BM suppression primarily via induction of HSC senescence , and oncogene induces accumulation of ROS and DNA damage and subsequently cellular senescence , which functions as an important barrier to prevent the growth of transformed cells to form a neoplasia . Here we investigated whether MDS CD34(+) cells enriched with HSC and HPC undergo senescence through accumulation of ROS and DNA damage and their action mechanisms . In this study , the percentages of SA-β-gal positive senescent CD34(+) cells increased in lower-risk MDS patients , but not in higher-risk MDS and AML patients , compared to that of healthy controls . The increases were associated with an elevated expression of p21 but not the activation of p38 . Further study found that there were increased ROS and DNA damage in CD34(+)CD38(-) cells enriched with HSC progression from lower-risk MDS , higher-risk MDS to AML . Therefore , these data suggest that CD34(+) cells from patients with lower-risk MDS present p21 dependent premature senescence , increased accumulation of ROS and DNA damage in CD34(+)CD38(-) cells could contribute to this process ; however , CD34(+) cells from patients with higher-risk MDS could develop some mechanisms to uncouple ROS and DNA damage induced senescence . OUTPUT:

enabling replicative immortality;avoiding immune destruction;genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot274

***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: The endothelial cell-specific microRNA ( miRNA ) , miR-126 , is considered a master regulator of physiological angiogenesis . Transplanted mesenchymal stem cells ( MSCs ) release soluble factors contributing to neoangiogenesis and cardiac repair . Therefore , we hypothesized that the over-expression of miR-126 may prolong MSC survival and enhance the cell secretome , thereby improving post-infarction angiogenesis and cardiac function . In this study , MSCs harvested from male C57BL/6 mouse bone marrow were infected in vitro with miR-126 ( MSC(miR-126) ) by using recombinant lentiviral vectors ; the control cells were either non-transfected or transduced with mock vectors ( MSC(null) ) . The results showed an increased secretion of angiogenic factors and a higher resistance against hypoxia in MSC(miR-126) compared with the control cells . The expression of the Notch ligand Delta-like ( Dll)-4 in the MSC(miR-126) group was also increased . For in vivo experiments , MSC(miR-126) cultures were intramyocardially injected into the infarct region of the hearts of female C57BL/6 mice ( an acute myocardial infarction model ) who had undergone ligation of the left anterior descending coronary artery . The survival of MSC(miR-126) cultures , determined by Sry expression , was increased at 7 days after transplantation . MSC(miR-126)-treated animals showed significantly improved cardiac function as assessed by echocardiography 2 weeks later . The expression levels of angiogenic factors and Dll-4 in the infarcted myocardium were further increased by MSC(miR-126) compared with MSCs or MSC(null) cultures . Furthermore , fluorescent microsphere and histological studies revealed that myocardial blood flow and microvessel density were significantly increased in the MSC(miR-126)-transplanted animals . In addition , we found increased immature vessel proliferation following the transplantation of MSC(miR-126) cultures in which the expression of Dll-4 had been knocked down . However , blood vessels with lumen were barely detected , which indicated that Dll-4 plays a key role in tubulogenesis . We conclude that the transplantation of MSCs overexpressing miR-126 can further enhance functional angiogenesis in the ischemic myocardium possibly by the secretion of angiogenic factors and the activation of Dll-4 , thus increasing MSC survival . Therefore , MSCs modified with miR-126 may represent a novel and efficient therapeutic approach for ischemic angiogenesis and the improvement of cardiac function . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot275

***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: p38 kinases activated by growth factors , hormones , and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology . Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer , although the mechanistic basis for this association is poorly understood . In this study , we report that p38 activation in cervical cancer cells is driven by osteopontin ( OPN ) , an extracellular matrix-associated cytokine that drives invasive progression . OPN regulates CD44-mediated p38 phosphorylation that induces NF-κB activation and NF-κB-dependent expression of furin , an extracellular protease implicated in human papilloma virus ( HPV ) processing that enhances cervical cancer cell motility . OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells . OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6 , p38α/β or NF-κB signaling . In a mouse xenograft model of human cervical cancer , tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA ( shRNA)-mediated OPN silencing . Furin overexpression similarly augmented tumor growth in the model , whereas blocking MKK3/6 , p38 , or furin reduced OPN-induced cervical tumor growth . Analysis of clinical specimens revealed that enhanced expression of OPN , phosphorylated NF-κB , p65 , and furin correlated with cervical cancer progression , further strengthening the in vitro and in vivo results . In summary , our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer . OUTPUT: sustaining proliferative signaling INPUT: BACKGROUND : The p38α MAP kinase pathway is involved in inflammation , cell differentiation , growth , apoptosis and production of pro-inflammatory cytokines TNF-α and IL-1β . The overproduction of these cytokines plays an important role in cancer . The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38α . METHODS : A tetrapeptide , VWCS as p38α inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling . The inhibition study of peptide with p38α was performed by ELISA , binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry . RESULTS : The percentage inhibition of designed VWCS against pure p38α protein and serum of HNSCC patients was 70.30 and 71.5% , respectively . The biochemical assay demonstrated the K(D) and IC(50) of the selective peptide as 7.22�10(-9)M and 20.08nM , respectively . The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC(50) value of 10μM and induced apoptosis by activating Caspase 3 and 7 . CONCLUSIONS : VWCS efficiently interacted at the ATP binding pocket of p38α with high potency and can be used as a potent inhibitor in case of HNSCC . GENERAL SIGNIFICANCE : VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner . Hence , p38α MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer . OUTPUT:

resisting cell death

HoC_dynamic_1_shot276

***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 carcinomas are defined by recurrent chromosomal aneuploidies , which result in a tissue-specific distribution of genomic imbalances . In order to develop models for these genome mutations and to determine their role in tumorigenesis , we generated 45 spontaneously transformed murine cell lines from normal epithelial cells derived from bladder , cervix , colon , kidney , lung , and mammary gland . Phenotypic changes , chromosomal aberrations , centrosome number , and telomerase activity were assayed in control uncultured cells and in three subsequent stages of transformation . Supernumerary centrosomes , binucleate cells , and tetraploidy were observed as early as 48 hr after explantation . In addition , telomerase activity increased throughout progression . Live-cell imaging revealed that failure of cytokinesis , not cell fusion , promoted genome duplication . Spectral karyotyping demonstrated that aneuploidy preceded immortalization , consisting predominantly of whole chromosome losses ( 4 , 9 , 12 , 13 , 16 , and Y ) and gains ( 1 , 10 , 15 , and 19 ) . After transformation , focal amplifications of the oncogenes Myc and Mdm2 were frequently detected . Fifty percent of the transformed lines resulted in tumors on injection into immunocompromised mice . The phenotypic and genomic alterations observed in spontaneously transformed murine epithelial cells recapitulated the aberration pattern observed during human carcinogenesis . The dominant aberration of these cell lines was the presence of specific chromosomal aneuploidies . We propose that our newly derived cancer models will be useful tools to dissect the sequential steps of genome mutations during malignant transformation , and also to identify cancer-specific genes , signaling pathways , and the role of chromosomal instability in this process . OUTPUT: enabling replicative immortality;genomic instability and mutation INPUT: MYC deregulation is common in human cancer . IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders . Deregulated expression of MYC results in increased mTOR complex 1 ( mTORC1 ) signaling . As tumors with mTORC1 activation are sensitive to mTORC1 inhibition , we used everolimus , a potent and specific mTORC1 inhibitor , to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma . Everolimus selectively cleared premalignant B cells from the bone marrow and spleen , restored a normal pattern of B-cell differentiation , and strongly protected against lymphoma development . Established Eμ-Myc lymphoma also regressed after everolimus therapy . Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity . Therefore , mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot277

***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: Extensive biochemical and structural analyses have been performed on the putative DNA repair proteins of hyperthermophilic archaea , in contrast to the few genetic analyses of the genes encoding these proteins . Accordingly , little is known about the repair pathways used by archaeal cells at high temperature . Here , we attempted to disrupt the genes encoding the potential repair proteins in the genome of the hyperthermophilic archaeon Thermococcus kodakaraensis . We succeeded in isolating null mutants of the hjc , hef , hjm , xpb , and xpd genes , but not the radA , rad50 , mre11 , herA , nurA , and xpg/fen1 genes . Phenotypic analyses of the gene-disrupted strains showed that the xpb and xpd null mutants are only slightly sensitive to ultraviolet ( UV ) irradiation , methyl methanesulfonate ( MMS ) and mitomycin C ( MMC ) , as compared with the wild-type strain . The hjm null mutant showed sensitivity specifically to mitomycin C. On the other hand , the null mutants of the hjc gene lacked increasing sensitivity to any type of DNA damage . The Hef protein is particularly important for maintaining genome homeostasis , by functioning in the repair of a wide variety of DNA damage in T. kodakaraensis cells . Deletion of the entire hef gene or of the segments encoding either its nuclease or helicase domain produced similar phenotypes . The high sensitivity of the Δhef mutants to MMC suggests that Hef performs a critical function in the repair process of DNA interstrand cross-links . These damage-sensitivity profiles suggest that the archaeal DNA repair system has processes depending on repair-related proteins different from those of eukaryotic and bacterial DNA repair systems using homologous repair proteins analyzed here . OUTPUT: genomic instability and mutation INPUT: The activity of DNA methyltransferase 1 ( DNMT1 ) is associated with diverse biological activities , including cell proliferation , senescence and cancer development . Here , we demonstrated that the HMG box-containing protein 1 ( HBP1 ) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence . The DNMT1 gene contains an HBP1-binding site at position -115 to -134bp from the transcriptional start site . HBP1 repressed the endogenous DNMT1 gene through sequence-specific binding , resulting in both gene-specific ( e.g. p16(INK4) ) and global DNA hypomethylation changes . The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence , the latter of which could be induced by Ras and HBP1 itself . A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions-both of which contribute to premature senescence . HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence . The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation . While intricate , the reciprocal partnership between HBP1 and DNMT1 has exceptional importance , since its abrogation compromises senescence and promotes tumorigenesis . Together , our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence with an impact on overall DNA methylation state . OUTPUT:

enabling replicative immortality

HoC_dynamic_1_shot278

***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: The aim of the present work was to study the expression of the proinflammatory cytokine , interleukin-6 ( IL-6 ) , mediated by bFGF signaling and its possible crosstalk with prostate-specific membrane antigen ( PSMA ) in LNCaP and PC3-PSMA prostate cancer cell lines . PC3 cells stably transfected with PSMA gene were used for restoring PSMA expression . LNCaP and PC3-PSMA cells were exposed to 10ng/mL of basic fibroblast growth factor ( bFGF ) . IL-6 production was measured by ELISA assay , and levels of PSMA expression were assessed by flow cytometry . AKT , ERK1/2 , and p38 phosphorylation were detected by Western blot. bFGF enhances IL-6 production in LNCaP and PC3-PSMA prostate cancer cells . The effect of bFGF on stimulating IL-6 secretion was greater in LNCaP than in PC3-PSMA cells . In the presence of bFGF , PSMA expression was activated after 4days of treatment in LNCaP and PC3-PSMA cells . This activation was not maintained after long term of treatment in both metastatic cell lines . Solely MAPKs pathways ( ERK1/2 and p38 ) were activated after bFGF stimulation in both metastatic cell lines , whereas AKT did not show any activation . The interference of the proinflammatory cytokine , IL-6 , with bFGF signaling and PSMA , should be of high clinical relevance in the treatment of metastatic prostate cancer . In developing novel therapeutic modalities targeting IL-6 , significant attention should be given to PSMA and its inactivation to fight against prostate cancer . OUTPUT:

activating invasion and metastasis;tumor promoting inflammation

HoC_dynamic_1_shot279

***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: MicroRNAs ( miRNAs ) are involved in cancer development and progression , acting as tumor suppressors or oncogenes . In this study , miRNA profiling was performed on 10 paired bladder cancer ( BC ) tissues using 20 GeneChipTM miRNA Array , and 10 differentially expressed miRNAs were identified in BC and adjacent noncancerous tissues of any disease stage/grade . After validated on expanded cohort of 67 paired BC tissues and 10 human BC cell lines by qRT-PCR , it was found that miR-100 was down-regulated most significantly in cancer tissues . Ectopic restoration of miR-100 expression in BC cells suppressed cell proliferation and motility , induced cell-cycle arrest in vitro , and inhibited tumorigenesis in vivo both in subcutaneous and intravesical passage . Bioinformatic analysis showed that mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in BC cell lines . In addition , the cancerous metastatic nude mouse model established on the basis of primary BC cell lines suggested that miR-100/mTOR regulated cell motility and was associated with tumor metastasis . Both mTOR and p70S6K ( downstream messenger ) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in primary tumor . Taken together , miR-100 may act as a tumor suppressor in BC , and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes . OUTPUT: evading growth suppressors;sustaining proliferative signaling;activating invasion and metastasis INPUT: MicroRNAs ( miRNAs or miR ) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes . The miR-124 was reported to be attenuated in several tumors , such as glioma , medulloblastoma and hepatocellular carcinoma . However , its role in cancer remains greatly elusive . In this study , we show that the miR-124 expression is significantly suppressed in human breast cancer specimens , which is reversely correlated to histological grade of the cancer . More intriguingly , ectopic expression of miR-124 in aggressive breast cancer cell lines MDA-MB-231 and BT-549 strongly inhibits cell motility and invasive capacity , as well as the epithelial-mesenchymal transition process . Also , lentivirus-delivered miR-124 endows MDA-MB-231 cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo . Further studies have identified the E-cadherin transcription repressor Slug as a direct target gene of miR-124 ; its downregulation by miR-124 increases the expression of E-cadherin , a hallmark of epithelial cells and a repressor of cell invasion and metastasis . Moreover , knockdown of Slug notably impairs the motility of MDA-MB-231 cells , whereas re-expression of Slug abrogates the reduction of motility and invasion ability induced by miR-124 in MDA-MB-231 cells . These findings highlight an important role for miR-124 in the regulation of invasive and metastatic potential of breast cancer and suggest a potential application of miR-124 in cancer treatment . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot280

***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 . Multiple myeloma ( MM ) , an almost incurable disease , is the second most common blood cancer . Initial chemotherapeutic treatment could be successful ; however , resistance development urges the use of higher toxic doses accompanied by hematopoietic stem cell transplantation . The establishment of more effective treatments that can overcome or circumvent chemoresistance has become a priority . We recently demonstrated that venom extracted from Walterinnesia aegyptia ( WEV ) either alone or in combination with silica nanoparticles ( WEV+NPs ) mediated the growth arrest and apoptosis of prostate cancer cells . In the present study , we evaluated the impact of WEV alone and WEV+NP on proliferation and apoptosis of MM cells . Methods . The impacts of WEV alone and WEV+NP were monitored in MM cells from 70 diagnosed patients . The influences of WEV and WEV+NP were assessed with flow cytometry analysis . Results . WEV alone and WEV+NP decreased the viability of MM cells . Using a CFSE proliferation assay , we found that WEV+NP strongly inhibited MM cell proliferation . Furthermore , analysis of the cell cycle using the propidium iodide ( PI ) staining method indicated that WEV+NP strongly altered the cell cycle of MM cells and enhanced the induction of apoptosis . Conclusions . Our data reveal the biological effects of WEV and WEV+NP on MM cells that enable these compounds to function as effective treatments for MM . OUTPUT: sustaining proliferative signaling;resisting cell death INPUT: Multiple myeloma ( MM ) is a clonal disease of plasma cells that remains incurable despite the advent of several novel therapeutics . In this study , we aimed to delineate the impact of snake venom extracted from Walterinnesia aegyptia ( WEV ) alone or in combination with silica nanoparticles ( WEV+NP ) on primary MM cells isolated from patients diagnosed with MM as well as on two MM cell lines , U266 and RPMI 8226 . The IC(50) values of WEV and WEV+NP that significantly decreased MM cell viability without affecting the viability of normal peripheral mononuclear cells ( PBMCs ) were determined to be 25 ng/ml and 10 ng/ml , respectively . Although both WEV ( 25 ng/ml ) and WEV+NP ( 10 ng/ml ) decreased the CD54 surface expression without affecting the expression of CXCR4 ( CXCL12 receptor ) on MM cells , they significantly reduced the ability of CXC chemokine ligand 12 ( CXCL12 ) to induce actin cytoskeleton rearrangement and the subsequent reduction in chemotaxis . It has been established that the binding of CXCL12 to its receptor CXCR4 activates multiple intracellular signal transduction pathways that regulate MM cell chemotaxis , adhesion , and proliferation . We found that WEV and WEV+NP clearly decreased the CXCL12/CXCR4-mediated activation of AKT , ERK , NFκB and Rho-A using western blot analysis ; abrogated the CXCL12-mediated proliferation of MM cells using the CFSE assay ; and induced apoptosis in MM cell as determined by PI/annexin V double staining followed by flow cytometry analysis . Monitoring the expression of B-cell CCL/Lymphoma 2 ( Bcl-2 ) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2 , Bcl(XL) and Mcl-1 ; conversely increased the expression of the pro-apoptotic effectors Bak , Bax and Bim ; and altered the mitochondrial membrane potential in MM cells . Taken together , our data reveal the biological effects of WEV and WEV+NP and the underlying mechanisms against myeloma cancer cells . OUTPUT:

resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot281

***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: It is now largely accepted that ribosomal proteins may be implicated in a variety of biological functions besides that of components of the translation machinery . Many evidences show that a subset of ribosomal proteins are involved in the regulation of the cell cycle and apoptosis through modulation of p53 activity . In addition , p53-independent mechanisms of cell cycle arrest in response to alterations of ribosomal proteins availability have been described . Here , we identify human rpL3 as a new regulator of cell cycle and apoptosis through positive regulation of p21 expression in a p53-independent system . We demonstrate that the rpL3-mediated p21 upregulation requires the specific interaction between rpL3 and Sp1 . Furthermore , in our experimental system , p21 overexpression leads to a dual outcome , activating the G₁/S arrest of the cell cycle or the apoptotic pathway through mitochondria , depending on its intracellular levels . It is noteworthy that depletion of p21 abrogates both effects . Taken together , our findings unravel a novel extraribosomal function of rpL3 and reinforce the proapoptotic role of p21 in addition to its widely reported ability as an inhibitor of cell proliferation . OUTPUT:

evading growth suppressors;resisting cell death

HoC_dynamic_1_shot282

***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: Cytokine-dependent cell lines have been used to analyze the cytokine-induced cellular signaling and the mechanism of oncogenesis . In the current study , we analyzed MOTN-1 and PLT-2 cell lines established from different stages of a T-cell large granular lymphocyte leukemia patient ( Daibata et al. 2004 ) . MOTN-1 is IL-2-dependent derived from the chronic phase , whereas IL-2-independent PLT-2 is from the aggressive and terminal stage . They shared considerable chromosome abnormalities and the pattern of T-cell receptor rearrangement , presuming that the cytokine independence of PLT-2 was due to the additive genetic abnormality . Besides IL-2 , IL-15 supported MOTN-1 cell growth , because these receptors share beta- and gamma-subunits . IL-2 activated ERK , AKT and STAT pathway of MOTN-1 . STAT3 pathway of PLT-2 was also activated by IL-2 , suggesting intact IL-2 induces signal transduction of PLT-2 . However , ERK1/2 but not AKT , was continuously activated in PLT-2 , consistent with the increased Ras-activity of PLT-2 . Sequence analysis revealed KRAS G12A mutation but not NRAS and HRAS mutation of PLT-2 but not MOTN-1 . Another signaling molecule affecting Ras-signaling pathway , SHP2 , which has been frequently mutated in juvenile myelomonocytic leukemia ( JMML ) , did not show mutation . Moreover , MEK inhibitor , PD98059 , as well as farnesylation inhibitor inhibited PLT-2 cell growth . Using NIH3T3 and MOTN-1 , ERK activation , increased cell proliferation and survival by KRAS G12A were shown , suggesting the important role of KRAS G12A in IL-2-independent growth of PLT-2 . Taken together , KRAS G12A is important for IL-2-independent growth of PLT-2 cells and suggests the possibility of involvement of KRAS mutation with disease progression . OUTPUT: genomic instability and mutation INPUT: Cancer immunotherapies are designed to elicit T-cell responses that inhibit tumor growth . Previous studies have demonstrated that interleukin 21 ( IL-21 ) is a promising cytokine for cancer immunotherapy due to its ability to induce the immunity of T cells and natural killer cells , whereas blockade of the interaction of programmed death receptor-1 ( PD-1 ) with its ligand ( PD-L1 ) reduces peripheral tolerance . In the current study , we investigated IL-21 alone and in combination with soluble PD-1 ( sPD-1 ) for the treatment of experimental H22 murine hepatocarcinoma . The naked plasmids pmIL-21 and/or psPD-1 were used for local gene transfer by injection . In these assays , sPD-1 combined with IL-21 was found to significantly inhibit the growth of the tumors in mice . Combined treatment with IL-21 and sPD-1 enhanced the antitumor immune response compared with that induced by IL-21 alone . Combined treatment was found to increase CTL cytotoxicity , increase the number of CTLs and NK cells in splenocytes , upregulate the cytokines IFN-γ and IL-2 and downregulate IL-10 . Thus , immunotherapy with IL-21 in combination with sPD-1 was found to induce a more efficacious antitumor immune response , which may have potential clinical implications . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot283

***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: Radiotherapy is a useful component of treatment strategies for esophageal cancer . The role of autophagy in response to ionizing radiation was investigated in human esophageal squamous carcinoma cells . Cell viability and clonogenic survival assay were used to evaluate the radiosensitivity of autophagy inhibitor ( 3-MA ) on esophageal squamous carcinoma cells . The percentage of apoptotic cells and cell cycle analysis were assessed by flow cytometry ; DAPI staining was used to detect apoptotic cells . The expression of beclin-1 and LC3 was measured using a Western blot . The ultrastructural analysis was under the electron microscope. 6 Gy irradiation induced a massive accumulation of autophagosomes accompanied by strong upregulation of beclin-1 and LC3-II expression in TE-1 cells . Compared with radiation alone , 3-MA combined with radiation significantly decreased cell viability , as well as autophagic ratio , beclin-1 , and LC3-II protein level . Inhibition of autophagy increased radiation-induced apoptosis and the percentage of G2/M-phase cells . Blockade of autophagy with 3-MA enhanced cytotoxicity of radiotherapy in human esophageal squamous carcinoma cells . It suggests that inhibition of autophagy could be used as adjuvant therapy to treat esophageal squamous cell carcinoma . OUTPUT: resisting cell death INPUT: Cancer therapy with rapamycin has been successfully implemented for kidney cancer , glioblastoma and prostate cancer . However , there are few studies concerning the effects of rapamycin on the treatment of human melanoma . In this study , we investigated whether rapamycin may be a promising strategy for the effective treatment of melanoma and explored the possible mechanism for this by culturing M14 cells in vitro and treating with rapamycin at three concentrations ( 10 , 50 or 100 nmol/l ) . MDC and LC3B staining , western blot analysis , flow cytometry and transmission electron microscopy were employed . We revealed that rapamycin induced autophagy and inhibited the proliferation of M14 cells in a concentration-dependent manner , Furthermore , western blot analysis revealed an upregulated expression of Bcl-2 and downregulated expression of Bax in M14 cells . In conclusion , rapamycin induced autophagy and inhibited the growth of M14 cells . The mechanism may involve regulation of the expression of Bcl-2 family proteins . Rapamycin appears to be a promising strategy for the effective treatment of melanoma . OUTPUT:

resisting cell death

HoC_dynamic_1_shot284

***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: The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy . There are few tools to predict chemoresponse or toxicity in cancer patients . We investigated the correlation between the induction and repair of DNA double-strand breaks ( DSBs ) using constant-field gel electrophoresis ( CFGE ) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil ( 5FU ) . Using a sulphorhodamine-B assay , colon carcinoma cells ( HCT116 ) were found to be the most sensitive to 5FU , followed by liver carcinoma cells ( HepG2 ) and breast carcinoma cells ( MCF-7 ) . Cervical carcinoma cells ( HeLa ) were the most resistant . As measured by CFGE , DSB induction , but not residual DSBs , exhibited a significant correlation with the sensitivity of the cell lines to 5FU . Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU . Another 5FU-induced cell cycle change in HCT116 , HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle . In addition , 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases . Determination of Fas ligand ( Fas-L ) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis , respectively , revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L ( extrinsic pathway ) . Therefore , the induction of DNA DSBs by 5FU , detected using CFGE , and the induction of apoptosis are candidate predictive markers that may distinguish cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome . OUTPUT:

evading growth suppressors;sustaining proliferative signaling;resisting cell death;genomic instability and mutation

HoC_dynamic_1_shot285

***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 Natural herbal compounds with novel actions different from existing breast cancer ( BCa ) treatment modalities are attractive for improving therapeutic efficacy and safety . We have recently shown that penta-1,2,3,4,6-O-galloyl-β-D-glucose ( PGG ) induced S-phase arrest in prostate cancer ( PCa ) cells through inhibiting DNA replicative synthesis and G(1) arrest , in addition to inducing cell death at higher levels of exposure . We and others have shown that PGG through intraperitoneal ( i.p. ) injection exerts a strong in vivo growth suppression of human PCa xenograft models in athymic nude mice . This study aims to test the hypothesis that the novel targeting actions of PGG are applicable to BCa cells , especially those lacking proven druggable targets . METHODS Mono-layer cell culture models of p53-wild type estrogen receptor ( ER)-dependent MCF-7 BCa cells and p53-mutant ER-/progesterone receptor ( PR)- and Her2-regular ( triple-negative ) MDA-MB-231 BCa were exposed to PGG for a comprehensive investigation of cellular consequences and molecular targets/mediators . To test the in vivo efficacy , female athymic mice inoculated with MDA-MB-231 xenograft were treated with 20mg PGG/kg body weight by daily gavage starting 4 days after cancer cell inoculation . RESULTS Exposure to PGG induced S-phase arrest in both cell lines as indicated by the lack of 5-bromo2'-deoxy-uridine ( BrdU ) incorporation into S-phase cells as well as G(1) arrest . Higher levels of PGG induced more caspase-mediated apoptosis in MCF-7 , in strong association with induction of P53 Ser(15) phosphorylation , than in MDA-MB-231 cells . The cell cycle arrests were achieved without an induction of cyclin dependent kinase ( CDK ) inhibitory proteins P21(Cip1) and P27(Kip1) . PGG treatment led to decreased cyclin D1 in both cell lines and over-expressing cyclin D1 attenuated G(1) arrest and hastened S arrest . In serum-starvation synchronized MCF-7 cells , down-regulation of cyclin D1 was associated with de-phosphorylation of retinoblastoma ( Rb ) protein by PGG shortly before G(1)-S transition . In vivo , oral administration of PGG led to a greater than 60% inhibition of MDA-MB231 xenograft growth without adverse effect on host body weight . CONCLUSIONS Our in vitro and in vivo data support PGG as a potential drug candidate for breast cancer with novel targeting actions , especially for a triple negative BCa xenograft model . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: BACKGROUND Sorafenib has recently been shown to reduce tumour growth in hepatoblastoma ( HB ) xenografts . The effect of a combined administration with cytostatic agents was now investigated . METHODS Cell viability after treatment with sorafenib and different cytostatic agents was evaluated in two HB cell lines ( HUH6 and HepT1 ) using MTT assay . ERK signalling was investigated by western blot , NOXA expression by rt-PCR , and formation of DNA adducts using immunocytology . NMRI mice bearing subcutaneous HUH6-derived tumours were treated with sorafenib alone or in combination with cisplatin . Tumour progression , viability , apoptosis , and vascularisation were monitored by tumour volume , AFP levels , TUNEL assay , and CD31 immunostaining , respectively . RESULTS The combination of sorafenib and cisplatin led to a remarkable decrease in cell viability . The cisplatin-induced enhanced ERK1/2 activation , but not NOXA expression and the formation of DNA adducts was partly abrogated by sorafenib . In HB xenografts , both , sorafenib and alternated application of sorafenib and cisplatin significantly reduced tumour growth ( P<0.05 ) . Levels of AFP were lower in both treated groups ( P=0.08 ) . Relative apoptotic areas were increased ( P=0.003 ) . Mean vascular density was the lowest in the sorafenib/CDDP group ( P=0.02 ) . CONCLUSION The combination of sorafenib with cisplatin might be a promising treatment option for high risk or recurrent HB . OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot286

***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 Adult human mesenchymal stem cells ( hMSC ) have been shown to home to sites of carcinoma and affect biological processes , including tumour growth and metastasis . Previous findings have been conflicting and a clear understanding of the effects of hMSCs on cancer remains to be established . Therefore , we set out to investigate the impact of hMSCs on the oestrogen receptor positive , hormone-dependent breast carcinoma cell line MCF-7 . RESULTS In this study , we show the effects of hMSCs on cancer cells are mediated through a secreted factor(s) which are enhanced by cancer cell-hMSC contact/communication . In addition to enhanced proliferation when in co-culture with hMSCs , MCF-7 cells were found to have increased migration potential in vitro . Inhibition of ER signalling by the pure anti-oestrogen ICI 182,780 decreased the effect of hMSCs on MCF-7 cell proliferation and migration supporting a role for ER signalling in the hMSC/MCF-7 cell interaction . Additionally , hMSCs have been shown to secrete a wide variety of growth factors and chemokines including stromal cell-derived factor-1 ( SDF-1 ) . This coupled with the knowledge that SDF-1 is an ER-mediated gene linked with hormone-independence and metastasis led to the investigation of the SDF-1/CXCR4 signalling axis in hMSC-MCF-7 cell interaction . Experiments revealed an increase in SDF-1 gene expression both in vivo and in vitro when MCF-7 cells were cultured with hMSCs . SDF-1 treatment of MCF-7 cells alone increased proliferation to just below that seen with hMSC co-culture . Additionally , blocking SDF-1 signalling using a CXCR4-specific inhibitor decreased hMSC induced proliferation and migration of MCF-7 . However , the combined treatment of ICI and AMD3100 reduced MCF-7 cell proliferation and migration below control levels , indicating targeting both the ER and CXCR4 pathways is effective in decreasing the hMSCs induction of MCF-7 cell proliferation and migration . CONCLUSIONS The sum of these data reveals the relationship between tumour microenvironment and tumour growth and progression . Better understanding of the mechanisms involved in this tumour stroma cell interaction may provide novel targets for the development of treatment strategies for oestrogen receptor positive , hormone-independent , and endocrine-resistant breast carcinoma . OUTPUT: activating invasion and metastasis;sustaining proliferative signaling INPUT: Our study was to elucidate the mechanisms whereby BMS-345541 ( BMS , a specific IκB kinase β inhibitor ) inhibits the repair of DNA double-strand breaks ( DSBs ) and evaluate whether BMS can sensitize MCF-7 breast cancer cells ( MCF-7 cells ) to ionizing radiation ( IR ) in an apoptosis-independent manner . In this study , MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS . The effects of BMS on the repair of IR-induced DSBs by homologous recombination ( HR ) and non-homologous end-joining ( NHEJ ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced γ-H2AX , 53BP1 , Brca1 and Rad51 foci assays . The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR . The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model . The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells , most likely by down-regulation of several genes that participate in HR . This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner . Furthermore , BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs . These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy . OUTPUT:

genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot287

***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 development of targeted therapies and immunotherapies has markedly advanced the treatment of metastasized melanoma . While treatment with selective BRAF(V600E) inhibitors ( like vemurafenib or dabrafenib ) leads to high response rates but short response duration , CTLA-4 blocking therapies induce sustained responses , but only in a limited number of patients . The combination of these diametric treatment approaches may further improve survival , but pre-clinical data concerning this approach is limited . We investigated , using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice , whether BRAF(V600E) inhibition can synergize with anti-CTLA-4 mAb treatment , focusing on the interaction between the BRAF(V600E) inhibitor PLX4720 and the immune system . While PLX4720 treatment strongly decreased tumor growth , it did not induce cell death in BRAF(V600E)/PTEN(-/-) melanomas . More strikingly , PLX4720 treatment led to a decreased frequency of tumor-resident T cells , NK-cells , MDSCs and macrophages , which could not be restored by the addition of anti-CTLA-4 mAb . As this effect was not observed upon treatment of BRAF wild-type B16F10 tumors , we conclude that the decreased frequency of immune cells correlates to BRAF(V600E) inhibition in tumor cells and is not due to an off-target effect of PLX4720 on immune cells . Furthermore , anti-CTLA-4 mAb treatment of inducible melanoma mice treated with PLX4720 did not result in enhanced tumor control , while anti-CTLA-4 mAb treatment did improve the effect of tumor-vaccination in B16F10-inoculated mice . Our data suggest that vemurafenib may negatively affect the immune activity within the tumor . Therefore , the potential effect of targeted therapy on the tumor-microenvironment should be taken into consideration in the design of clinical trials combining targeted and immunotherapy . OUTPUT: avoiding immune destruction INPUT: In spite of the fact that they occur at high rates , the clinical responses of BRAF(V600) mutant metastatic melanoma to BRAF inhibitors are usually short-lasting , with most cases progressing within less than 8 mo . Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient . By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system , we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer , which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma . Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAF(V600) mutant melanoma cell lines in vitro . Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8(+) T cells . Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins . In conclusion , our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells . OUTPUT:

avoiding immune destruction

HoC_dynamic_1_shot288

***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: Recent studies indicate that cyclooxygenase-2 ( COX-2 ) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer . A human pancreatic adenocarcinoma cell line , Mia PaCa-2 , was incubated for 18 hours with 5 micromol/L of rofecoxib ( Vioxx ) , a selective COX-2 inhibitor . Total RNA was isolated and gene expression analyzed by DNA microarray chips . In a separate experiment , athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy . After 1 month , laparotomy was repeated to measure tumor size , and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days . Tumor growth was assessed by comparing volume before and after treatment . In vitro , rofecoxib decreased gene expression of cyclin D1/PRAD1 , a key component of cell cycle progression , while increasing expression of several cell cycle arrest genes , including p21/WAF1 , p33/ING , GADD34 , and GADD45 ( P &lt ; 0.05 ) . In vivo , tumor growth was significantly reduced in treated vs. control mice ( P &lt ; 0.05 ) . No systemic toxicity was observed in mice receiving rofecoxib . These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest . OUTPUT: evading growth suppressors;sustaining proliferative signaling INPUT: Abstract Different cyclooxygenase ( COX)-2 inhibitors were known to cause different cell cycle changes . We investigated whether this different effect on cell cycle change was due to concentration-dependent effect . We investigated the effects of celecoxib , a COX-2 selective inhibitor , on cell cycle regulation in irradiated cancer cells that express high or low levels of COX-2 . Four stably COX-2 knocked-down or overexpressed cell lines were treated with various concentrations of celecoxib with or without radiation . Celecoxib differentially modulated the cell cycle according to the concentrations applied . G(1) arrest was induced at lower concentrations , whereas G(2)/M arrest was induced at higher concentrations in each cell line tested . Radiation-induced G(2)/M arrest was enhanced at lower concentrations but reduced at higher concentrations . The cutoff values to divide lower and higher concentrations were cell-type specific . Celecoxib treatment activated Cdc25C and inhibited p21 expression in both unirradiated and irradiated cells , regardless of COX-2 expression . Apoptosis was induced in irradiated cells 48 hours after treatment with celecoxib dependent of COX-2 . These results imply that celecoxib deactivates the G(2) checkpoint via both Cdc25C- and p21-dependent pathways in irradiated cells , which subsequently die by secondary apoptosis . Cell cycle modulating effects in irradiated cells resulting from treatment with celecoxib may have clinical importance with regard to the potential application of celecoxib in cancer patients undergoing radiotherapy . OUTPUT:

evading growth suppressors;sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot289

***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 Chronic generation of inflammatory cytokines and reactive oxygen species are implicated in atherosclerosis , aging , cancers , and other chronic diseases . We hypothesized that zinc induces A20 in premonocytic , endothelial , and cancer cells , and A20 binds to tumor necrosis factor ( TNF)-receptor associated factor , and inhibits Iκ kinase-α ( IKK-α)/nuclear factor-κB ( NF-κB ) , resulting in downregulation of TNF-α and interleukin-1β ( IL-1β ) . METHODS To test this hypothesis , we used HL-60 , human umbilical vein endothelial cells , and SW480 cell lines under zinc-deficient and zinc-sufficient conditions in this study . We measured oxidative stress markers , inflammatory cytokines , A20 protein and mRNA , A20-FRAF-1 complex , and IKK-α/NF-κB signaling in stimulated zinc-deficient and zinc sufficient cells . We also conducted antisense A20 and siRNA studies to investigate the regulatory role of zinc in TNF-α and IL-1β via A20 . RESULTS We found that zinc increased A20 and A20-tumor necrosis factor-receptor associated factor-1 complex , decreased the IKK-α/NF-κB signaling pathway , oxidative stress markers , and inflammatory cytokines in these cells compared with zinc-deficient cells . We confirmed that zinc-induced A20 contributes to downregulation of TNF-α and IL-1β by antisense and short interfering RNA A20 studies . CONCLUSION Our studies suggest that zinc suppresses generation of NF-κB-regulated inflammatory cytokines by induction of A20 . OUTPUT: tumor promoting inflammation INPUT: The role of inflammatory cytokine interleukin-20 ( IL-20 ) has not yet been studied in cancer biology . Here , we demonstrated up-regulation of both IL-20 and IL-20R1 in muscle invasive bladder cancer ( MIBC ) patients . The expressions of IL-20 and IL-20R1 were observed in bladder cancer 5637 and T-24 cells . We found that IL-20 significantly increased the expression of matrix metalloproteinase ( MMP)-9 via binding activity of NF-κB and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2 , JNK , p38MAPK , and Jak-Stat signaling . Among the pathways examined , only ERK1/2 inhibitor U0126 significantly inhibited IL-20-induced migration and invasion . Moreover , siRNA knockdown of IL-20R1 suppressed migration , invasion , ERK1/2 activation , and NF-κB-mediated MMP-9 expression induced by IL-20 . Unexpectedly , cell cycle inhibitor p21WAF1 was induced by IL-20 treatment without altering cell cycle progression . Blockade of p21WAF1 function by siRNA reversed migration , invasion , activation of ERK signaling , MMP-9 expression , and activation of NF-κB in IL-20-treated cells . In addition , IL-20 induced the activation of IKK , the degradation and phosphorylation of IκBa , and NF-κB p65 nuclear translocation , which was regulated by ERK1/2 . IL-20 stimulated the recruitment of p65 to the MMP-9 promoter region . Finally , the IL-20-induced migration and invasion of cells was confirmed by IL-20 gene transfection and by addition of anti-IL-20 antibody . This is the first report that p21WAF1 is involved in ERK1/2-mediated MMP-9 expression via increased binding activity of NF-κB , which resulted in the induction of migration in IL-20/IL-20R1 dyad-induced bladder cancer cells . These unexpected results might provide a critical new target for the treatment of bladder cancer . OUTPUT:

activating invasion and metastasis;evading growth suppressors;sustaining proliferative signaling

HoC_dynamic_1_shot290

***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: Human CD93 , an epidermal growth factor ( EGF)-like domain containing transmembrane protein , is predominantly expressed in the vascular endothelium . Studies have shown that AA4 , the homolog of CD93 in mice , may mediate cell migration and angiogenesis in endothelial cells . Soluble CD93 has been detected in the plasma of healthy individuals . However , the role of soluble CD93 in the endothelium remains unclear . Recombinant soluble CD93 proteins with EGF-like domains ( rCD93D123 , with domains 1 , 2 , and 3 ; and rCD93D23 , with domains 2 and 3 ) were generated to determine their functions in angiogenesis . We found that rCD93D23 was more potent than rCD93D123 in stimulating the proliferation and migration of human umbilical vein endothelial cells ( HUVECs ) . Production of matrix-metalloproteinase 2 increased after the HUVECs were treated with rCD93D23 . Further , in a tube formation assay , rCD93D23 induced cell differentiation of HUVECs through phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase and extracellular signal-regulated kinases-1/2 signaling . Moreover , rCD93D23 promoted blood vessel formation in a Matrigel-plug assay and an oxygen-induced retinopathy model in vivo . Our findings suggest that the soluble EGF-like domain containing CD93 protein is a novel angiogenic factor acting on the endothelium . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot291

***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: Breast cancer is the second most common cancer with a high incidence rate worldwide . One of the promising therapeutic approaches on breast cancer is to use the drugs that target the estrogen receptor ( ER ) . In the present investigation , marmorin , a type I ribosome inactivating protein from the mushroom Hypsizigus marmoreus , inhibited the survival of breast cancer in vitro and in vivo . It evinced more potent cytotoxicity toward estrogen receptor ( ER)-positive MCF7 breast cancer cells than ER-negative MDA-MB-231 cells . Further study disclosed that marmorin undermined the expression level of estrogen receptor α ( ERα ) and significantly inhibited the proliferation of MCF7 cells induced by 17β-estradiol . Knockdown of ERα in MCF7 cells significantly attenuated the inhibitory effect of marmorin on proliferation , suggesting that the ERα-mediated pathway was implicated in the suppressive action of marmorin on ER-positive breast cancer cells . Moreover , marmorin induced time-dependent apoptosis in both MCF7 and MDA-MB-231 cells . It brought about G2/M-phase arrest , mitochondrial membrane potential depolarization and caspase-9 activation in MCF7 cells , and to a lesser extent in MDA-MB-231 cells . Marmorin triggered the death receptor apoptotic pathway ( e.g. caspase-8 activation ) and endoplasmic reticulum stress ( ERS , as evidenced by phosphorylation of PERK and IRE1α , cleavage of caspase-12 , and up-regulation of CHOP expression ) in both MCF7 and MDA-MB-231 cells . In summary , marmorin exhibited inhibitory effect on breast cancer partially via diminution of ERα and apoptotic pathways mediated by mitochondrial , death receptor and ERS . The results advocate that marmorin is a potential candidate for breast cancer therapy . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot292

***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 new cell line of human ovarian clear cell adenocarcinoma ( CCC ) , TU-OC-1 , was established and characterized . The cells showed a polygonal-shaped morphology and grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle . The chromosome numbers ranged from 64 to 90 . A low rate of proliferation was observed , similar to other CCC cell lines tested ( OVTOKO , RMG-I , and OVAS ) , and the doubling time was 38.4h . The respective IC50 values of cisplatin and paclitaxel were 12.2μM and 58.3nM . Mutational analysis revealed that TU-OC-1 cells harbored a PIK3CA mutation at codon 542 ( E542K ) in exon 9 , which is a mutation hot spot on this gene . We observed that phosphorylated Akt protein was overexpressed in TU-OC-1 cells by western blot analysis . Heterotransplantation to nude mice produced tumors that reflected the original . This cell line may be useful to study the chemoresistant mechanisms of CCC and contribute to novel treatment strategies . OUTPUT: genomic instability and mutation INPUT: A new line of human ovarian serous adenocarcinoma cells , TU-OS-4 , was established and characterized . The cells showed a short , spindle-shaped morphology and grew in monolayers without contact inhibition while forming an arrangement resembling a jigsaw puzzle . Chromosome numbers ranged from 55 to 73 . The proliferation rate was lower than other serous adenocarcinoma cell lines tested ( KF , SHIN-3 , and SK-OV-3 ) , and the doubling time was 53.3 h . Western blot analysis showed that TU-OS-4 cells overexpressed epidermal growth factor receptor , human epidermal growth factor receptor ( HER ) 2 , and phosphorylated HER2 protein . The IC(50) values to cisplatin , paclitaxel , and lapatinib were 25.8 μM , 686 nM , and 183 nM , respectively . Heterotransplantation in nude mice reflected the original tumor of the cells . These results suggested that this cell line would be useful to study chemoresistant mechanisms and contribute to establishing novel treatment strategies for patients with ovarian cancer . OUTPUT:

evading growth suppressors;sustaining proliferative signaling

HoC_dynamic_1_shot293

***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: N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer . Activating mutations in N-Ras occur in a subset of colorectal cancers , but little in known about how the mutant protein contributes to onset and progression of the disease . Using genetically engineered mice , we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation . The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function , which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3 . As a result , inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras . The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients . These data demonstrate for the first time the important role that N-Ras plays in colorectal cancer . OUTPUT:

resisting cell death;genomic instability and mutation

HoC_dynamic_1_shot294

***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: Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer ( NSCLC ) despite poor response rates and limited response duration . It has been reported that tumor expression of ERCC1 , a key component in nucleotide excision repair , may correlate with clinical response to platinum agents . We found that most primary lung tumor specimens demonstrated a stronger protein expression of poly ( ADP ribose ) polymerases 1 ( PARP1 ) than their normal counterparts . We therefore hypothesized that combining PARP inhibition with platinum compounds may be an approach to improve platinum-based therapy for NSCLC . Drug combination experiments revealed that two distinct PARP inhibitors , olaparib and veliparib not only potentiated the cell killing by cisplatin but also conferred cytotoxicity as a single agent specifically in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells . Moreover , siRNA knockdown of ERCC1 in A549 and H157 cells increased their sensitivities to both cisplatin and olaparib in a synergistic manner in our model . Furthermore , mechanistic studies indicated that combined PARP inhibitor and cisplatin could lead to sustained DNA double strand breaks , prolonged G2/M cell cycle arrest with distinct activation of checkpoint kinase 1 signaling , and more pronounced apoptosis preferentially in lung cancer cells with low ERCC1 expression . Collectively , these data suggest that there is a synergistic relationship between PARP inhibition and low ERCC1 expression in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression . OUTPUT:

evading growth suppressors;genomic instability and mutation;resisting cell death

HoC_dynamic_1_shot295

***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 BMP-6 , which belongs to the TGF-β superfamily , is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis . Our recent research has implied that BMP-6 may suppress breast cancer metastasis . In the present study , we extended to elucidate the molecular mechanism by which BMP-6 exerts its anti-tumorigenic effect . METHODS The Boyden chamber assay was used to examine the ability of BMP-6 and HO-1 in MCF-7 malignant progress . RT-PCR , western blot , luciferase assay , and quantitative CHIP were used to determine the potential mechanism and signaling pathways by which BMP-6 and HO-1 function as anti-metastatic factors in MCF-7 cells . RESULTS The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MCF-7 cells , which effect was significantly deprived by knockdown of HO-1 . We further demonstrated that BMP-6 treatment resulted in an activation of HO-1 transcription through the recruitment of Smad1/5 to the Smad-responsive element on its promoter . In addition , BMP-6-induced up-regulation of HO-1 exhibited an inhibitory effect on MMP-9 secretion in a paracrine action in MCF-7 cells . Overexpression of BMP-6 and HO-1 synergistically suppressed MMP-9 transcription , which effect was specifically mediated via the MAPK/p38/AP-1 signaling . However , blockade of HO-1 using ZnPPIX totally abolished BMP-6-regulated MMP-9 activation in MCF-7 cells . CONCLUSIONS These observations suggest a novel role of BMP-6/HO-1 cascade to relieve breast cancer metastasis by regulating the secretion of growth factors in tumor microenvironment . OUTPUT: activating invasion and metastasis;sustaining proliferative signaling INPUT: Bladder cancer ( BCa ) remained a major health problem . Med19 was related to tumor growth of BCa . Bone morphogenetic proteins ( BMPs ) were reported to be critical in bone metastasis of cancer . We therefore investigated the relations between Med19 and BMPs in BCa and their effect on bone metastasis of BCa . Bladder cancer cell lines were cultured and interfered with Med19 shRNA and control . Expressions of BMP-1 , BMP-2 , BMP-4 , BMP-5 , BMP-6 , BMP-7 , BMP-9 , and BMP-15 were studied between 2 groups . Fifty-two BCa samples were included for immunohistochemical staining of Med19 and BMP-2 . Expressions were scored and studied statistically . Invasiveness was studied with Transwell assay . Silencing or Med19 in BCa cells induced altered expressions of BMPs . Increased expressions of BMP-1 , BMP-4 , BMP-6 , BMP-7 , and BMP-15 and decreased expressions of BMP-2 , BMP-5 , and BMP-9 were noticed , but only BMP-2 reached statistical significance . Expressions of Med19 and BMP-2 were significantly higher in cases with bone metastasis and were positively correlated in cases with bone metastasis and muscle invasion . Med19 is a critical factor involved in the invasiveness and promotion of bone metastasis of BCa , possibly via BMP-2 . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot296

***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: Nectin-like molucule-5 ( Necl-5 ) is an immunoglobulin-like molecule that was originally identified as a poliovirus receptor and is often upregulated in cancer cells . It has been said that Necl-5 plays a role in not only cell-cell adhesion , but also cell migration , proliferation , and metastasis . In this study , we used a bronchioloalveolar carcinoma ( BAC ) cell line and fibroblasts to assess the expression of Necl-5 in the development of cancer-stroma communication by using an easy-to-prepare double-layered collagen gel hemisphere ( DL- CGH ) system that enables visualization of cell migration during invasion . The expression of Necl-5 was higher in BAC cells than in fibroblasts . This tendency didn't change even when the BAC cells were mixed with fibroblasts . To assess the role of Necl-5 in the invasive activity of the BAC cells , we knocked down its expression using RNA interference ( RNAi ) . The invasion assay with DL-CGH revealed that inhibitation of Necl-5 expression in the BAC cells was associated with suppressed invasiveness . In addition , Necl-5 knockdown inhibited the movement and proliferation of the BAC cells . Necl-5 expression in lung cancer cells is crucial for their invasiveness in the cancer-stromal interaction , suggesting that Necl-5 could be a favorable molecular target for the suppression of invasiveness in lung adenocarcinoma . OUTPUT:

activating invasion and metastasis;sustaining proliferative signaling

HoC_dynamic_1_shot297

***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: The Wnt/β-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells ( HNSCC ) . Increased β-catenin predisposes HNSCC patients to poor prognosis and survival . This study was conducted to determine the mechanism by which β-catenin regulates the viability of HNSCC . AMC-HN-3 , -HN-8 , UM-SCC-38 , and -SCC-47 cells , which were established from human head and neck cancer specimens , underwent cell death following β-catenin silencing. β-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3 , which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA . Intriguingly , β-catenin silencing also induced autophagy . Here , we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with β-catenin siRNA . These cell death modes are most likely due to the activation of LKB1-dependent AMPK following β-catenin silencing . The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling . In addition , treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against β-catenin silencing-induced cytotoxicity . Taken together , these results imply that following β-catenin silencing , HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK . To the best of our knowledge , these results suggest for the first time that novel crosstalk between β-catenin and the LKB1/AMPK pathway regulates the viability of HNSCC . This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in β-catenin silencing-induced cell death . OUTPUT:

resisting cell death

HoC_dynamic_1_shot298

***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: Transforming growth factor-beta1 ( TGF-beta1 ) exerts potent immunosuppressive effects . In this study , we investigated the potential role of TGF-beta1 produced by hepatocellular carcinoma ( HCC ) cell lines in immunosuppression mechanisms . Using the Mv1Lu cell-growth inhibition assay and an enzyme-linked immunosorbent assay ( ELISA ) , we detected optimal levels of TGF-beta1 in the culture supernatants conditioned by the HCC cell lines PLC/PRF/5 , Hep3B , and HepG2 . To determine the biological activity of TGF-beta1 in the supernatants , we examined the effects of the culture supernatants on the production of interferon ( IFN)-gamma induced during the culture of peripheral blood mononuclear cells ( PBMCs ) stimulated with interleukin ( IL)-12 . IFN-gamma production of IL-12-stimulated PBMCs in the 1:1 dilution of the acid-activated conditioned medium of PLC/PRF/5 , Hep3B , and HepG2 reduced to 14.7 +/- 0.8 , 17.3 +/- 9.0 , and 35.9 +/- 14.6% , respectively , compared with the value in the culture with control medium ( complete culture medium ) . These results suggest that HCC cells producing TGF-beta1 may reduce the generation or activation of cytotoxic T lymphocytes ( CTL ) and natural killer ( NK ) cells , and thus could enhance their ability to escape immune-mediated surveillance . OUTPUT: avoiding immune destruction INPUT: Growth differentiation factor-15 ( GDF-15 ) and the CCN family member , connective tissue growth factor ( CCN2 ) , are associated with cardiac disease , inflammation and cancer . The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive . Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2 . Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins . To investigate the functional consequences of this interaction , in vitro angiogenesis assays were performed . We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial ( HUVEC ) cells . To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis , activation of α(V) β(3) integrins and focal adhesion kinase ( FAK ) was examined . CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in α(V) β(3) integrin clustering in HUVEC cells . These results demonstrate , for the first time , a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2 . Furthermore , antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states . J. Cell . Biochem. � 2012 Wiley Periodicals , Inc . OUTPUT:

inducing angiogenesis

HoC_dynamic_1_shot299

***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: Advanced or metastatic prostate cancer is treated by androgen deprivation ; however , patients inevitably relapse with castration-resistant prostate cancer ( CRPC ) . CRPC remains dependent on androgen receptor ( AR ) signaling , which may include constitutive , ligand-independent action of naturally occurring AR splice variants . For example , the AR splice variant AR3 ( also termed AR-V7 ) is expressed in CRPC and is linked to poor prognosis . Vav3 , a Rho GTPase guanine nucleotide exchange factor , is an AR coactivator that is up-regulated in human prostate cancer compared with benign tissue and in preclinical models of CRPC . Vav3 confers castration-resistant growth to androgen-dependent human prostate cancer cells . Despite the importance of AR coactivators in promoting CRPC , the potential role of these regulatory proteins in modulating AR splice variant activity is unknown . We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3 . Vav3 or AR3 knockdown greatly attenuated cell proliferation , soft agar growth , and ligand-independent AR activity . Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevant AR splice variant , ARv567es . Vav3 knockdown resulted in lowered nuclear AR3 levels , whereas total AR3 levels remained similar . Conversely , overexpression of Vav3 resulted in increased nuclear AR3 . Coimmunoprecipitation revealed that AR3 and Vav3 interact . These novel data demonstrating physical and functional interactions between Vav3 , a unique AR coactivator , and an AR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC . OUTPUT: sustaining proliferative signaling INPUT: Elevated androgen receptor ( AR ) activity in castration-resistant prostate cancer ( CRPC ) may occur through increased levels of AR coactivator proteins . Vav3 , a guanine nucleotide exchange factor ( GEF ) , is upregulated following progression to castration-resistance in preclinical models and is overexpressed in a significant number of human prostate cancers . Vav3 is a novel coactivator of the AR . We sought to identify Vav3 binding partners in an effort to understand the molecular mechanisms underlying Vav3 enhancement of AR activity and to identify new therapeutic targets . The cell division cycle 37 homolog ( Cdc37 ) , a protein kinase-specific co-chaperone for Hsp90 , was identified as a Vav3 interacting protein by yeast two hybrid screening . Vav3-Cdc37 interaction was confirmed by GST pulldown and , for native proteins , by coimmunoprecipitation experiments in prostate cancer cells . Cdc37 potentiated Vav3 coactivation of AR transcriptional activity and Vav3 enhancement of AR amino-carboxyl terminal ( N-C ) interaction , which is essential for optimal receptor transcriptional activity . Cdc37 increased prostate cancer cell proliferation selectively in Vav3 expressing cells . Cdc37 did not affect Vav3 nucleotide exchange activity , Vav3 protein levels or subcellular localization . Disruption of Vav3-Cdc37 interaction inhibited Vav3 enhancement of AR transcriptional activity and AR N-C interaction . Diminished Vav3-Cdc37 interaction also caused decreased prostate cancer cell proliferation selectively in Vav3 expressing cells . Taken together , we identified a novel Vav3 interacting protein that enhances Vav3 coactivation of AR and prostate cancer cell proliferation . Vav3-Cdc37 interaction may provide a new therapeutic target in prostate cancer . OUTPUT:

sustaining proliferative signaling