bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer-Associated Transforming Growth Factor β Type II Receptor Gene Mutant Causes Activation of Bone Morphogenic Protein-Smads and Invasive Phenotype
Authors: Bharathy Savita , Xie Wen , Yingling Jonathan M. , Reiss Michael 
Published: March 2008

Abstract
Transforming growth factor β (TGFβ) plays a key role in maintaining tissue homeostasis by inducing cell cycle arrest, differentiation and apoptosis, and ensuring genomic integrity. Furthermore, TGFβ orchestrates the response to tissue injury and mediates repair by inducing epithelial to mesenchymal transition and by stimulating cell motility and invasiveness. Although loss of the homeostatic activity of TGFβ occurs early on in tumor development, many advanced cancers have coopted the tissue repair function to enhance their metastatic phenotype. How these two functions of TGFβ become uncoupled during cancer development remains poorly understood. Here, we show that, in human keratinocytes, TGFβ induces phosphorylation of Smad2 and Smad3 as well as Smad1 and Smad5 and that both pathways are dependent on the kinase activities of the type I and II TGFβ receptors (TβR). Moreover, cancer-associated missense mutations of the TβRII gene (TGFBR2) are associated with at least two different phenotypes. One type of mutant (TGFBR2E526Q) is associated with loss of kinase activity and all signaling functions. In contrast, a second mutant (TGFBR2R537P) is associated with high intrinsic kinase activity, loss of Smad2/3 activation, and constitutive activation of Smad1/5. Furthermore, this TGFBR2 mutant endows the carcinoma cells with a highly motile and invasive fibroblastoid phenotype. This activated phenotype is TβRI (Alk-5) independent and can be reversed by the action of a dual TβRI and TβRII kinase inhibitor. Thus, identification of such activated TβRII receptor mutations in tumors may have direct implications for appropriately targeting these cancers with selective therapeutic agents. [Cancer Res 2008;68(6):1656–66]
Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression
Authors: Blázquez Cristina , Salazar María , Carracedo Arkaitz , Lorente Mar , Egia Ainara , González-Feria Luis , Haro Amador , Velasco Guillermo , Guzmán Manuel 
Published: March 2008

Abstract
Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, but the molecular targets of this cannabinoid action remain elusive. Here, we evaluated the effect of cannabinoids on matrix metalloproteinase (MMP) expression and its effect on tumor cell invasion. Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid-induced inhibition of MMP-2 expression in gliomas (a) was MMP-2–selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB2 cannabinoid receptor–selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC-mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity. [Cancer Res 2008;68(6):1945–52]
Prediction of Cancer Driver Mutations in Protein Kinases
Authors: Torkamani Ali , Schork Nicholas J. 
Published: March 2008

Abstract
A large number of somatic mutations accumulate during the process of tumorigenesis. A subset of these mutations contribute to tumor progression (known as “driver” mutations) whereas the majority of these mutations are effectively neutral (known as “passenger” mutations). The ability to differentiate between drivers and passengers will be critical to the success of upcoming large-scale cancer DNA resequencing projects. Here we show a method capable of discriminating between drivers and passengers in the most frequently cancer-associated protein family, protein kinases. We apply this method to multiple cancer data sets, validating its accuracy by showing that it is capable of identifying known drivers, has excellent agreement with previous statistical estimates of the frequency of drivers, and provides strong evidence that predicted drivers are under positive selection by various sequence and structural analyses. Furthermore, we identify particular positions in protein kinases that seem to play a role in oncogenesis. Finally, we provide a ranked list of candidate driver mutations. [Cancer Res 2008;68(6):1675–82]
Thyroid Hormone Receptors Suppress Pituitary Tumor Transforming Gene 1 Activity in Hepatoma
Authors: Chen Ruey-Nan , Huang Ya-Hui , Yeh Chau-Ting , Liao Chen-Hsin , Lin Kwang-Huei 
Published: March 2008

Abstract
Pituitary tumor transforming gene 1 (PTTG1) is expressed in most tumors. However, whether thyroid hormone (T3) and its receptors (TR) regulate PTTG1 in human hepatocellular carcinomas (HCC) remains unclear. Previous cDNA microarrays revealed PTTG1 is down-regulated by T3/TR. This study investigated the significance of PTTG1 regulation by T3 in HCC cells. The PTTG1 mRNA and protein expression were repressed by T3 in HCC cell lines overexpressing TR. However, after knockdown of TRs expression by RNA interference, PTTG1 repression by T3 was abolished. Similar results were observed in thyroidectomized rats. To localize the regulatory region in the PTTG1 promoter, serial deletions within the PTTG1 promoter region were constructed. The promoter activity of the PTTG1 gene was repressed (25–51%) by T3. Additionally, these findings indicate that PTTG1 may be regulated by Sp1. The critical role of the −594 and −520 Sp1 binding sites was confirmed by electrophoretic mobility shift assay. Transfection with Sp1 expression vector enhanced the activity of the PTTG1 promoter fragment reporter. Also, Sp1 was down-regulated in HCC cells and in thyroidectomized rat after T3 treatment. Additionally, ectopic expression of PTTG1 promotes cell proliferation in Hep3B hepatoma cells. Conversely, knockdown of PTTG1 or Sp1 expression reduced cell proliferation in HepG2 cells. Notably, the expression of PTTG1 and Sp1 was inversely correlated with the expression of TR proteins in HCC. Together, these findings indicate that PTTG1 gene expression is mediated by Sp1 and is indirectly down-regulated by T3. Finally, overexpression of PTTG1 or SP1 in HCCs is TR-dependent and crucial in the development of HCC. [Cancer Res 2008;68(6):1697–1706]
Triggering Senescence Programs Suppresses Chk1 Kinase and Sensitizes Cells To Genotoxic Stresses
Authors: Gabai Vladimir L. , O'Callaghan-Sunol Cornelia , Meng Le , Sherman Michael Y. , Yaglom Julia 
Published: March 2008

Abstract
Depletion of the major heat shock protein Hsp72 leads to activation of the senescence program in a variety of tumor cell lines via both p53-dependent and p53-independent pathways. Here, we found that the Hsp72-depleted cells show defect in phosphorylation and activation of the protein kinase Chk1 by genotoxic stresses, such as UVC irradiation or camptothecin. Under these conditions, phosphorylation of Rad17 was also suppressed, whereas phosphorylation of p53 at Ser15 was not affected, indicating a specific defect in phosphorylation of a subset of the ATR kinase substrates. Similarly, suppression of Chk1 activation was seen when senescence signaling was triggered by direct stimulation of p53, depletion of Cdc2, or overexpression of the cell cycle inhibitors p21 or p16. Thus, defect in Chk1 activation was not a consequence of the chaperone imbalance, but rather a downstream effect of activation of the senescence signaling. Inhibition of Chk1 was associated with inefficient inter-S phase checkpoint, as Hsp72 depleted cells failed to halt cell cycle progression upon UVC irradiation. Accordingly, sensitivity of cells to genotoxic stimuli after Hsp72 depletion was significantly enhanced. Thus, activation of the senescence signaling causes a defect in the DNA damage response manifested in increased sensitivity to genotoxic stresses. [Cancer Res 2008;68(6):1834–42]
PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab
Authors: Jhawer Minaxi , Goel Sanjay , Wilson Andrew J. , Montagna Cristina , Ling Yi-He , Byun Do-Sun , Nasser Shannon , Arango Diego , Shin Joongho , Klampfer Lidija , Augenlicht Leonard H. , Soler Roman Perez , Mariadason John M. 
Published: March 2008

Abstract
Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G0-G1 arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 ± 5.0% versus 38.5 ± 6.4% growth inhibition, mean ± SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 ± 4.3% versus 38.8 ± 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy. [Cancer Res 2008;68(6):1953–60]
Therapy of Advanced Established Murine Breast Cancer with a Recombinant Adenoviral ErbB-2/neu Vaccine
Authors: Park Jong Myun , Terabe Masaki , Steel Jason C. , Forni Guido , Sakai Yoshio , Morris John C. , Berzofsky Jay A. 
Published: March 2008

Abstract
ErbB-2 (HER-2/neu) is a transforming oncogene expressed by a substantial fraction of breast cancers, and monoclonal antibody therapy directed toward this antigen is an established treatment modality. However, not all tumors respond, and with a monoclonal antibody directed to a single epitope, there is always the risk of tumor escape. Furthermore, passive antibody therapy requires continual treatment. Whereas cancer vaccines have prevented the growth of tumors, it has been far more difficult to treat large established tumors. Here, we show that vaccination with a recombinant adenovirus expressing a truncated ErbB-2 antigen can cure large established subcutaneous ErbB-2–expressing breast cancers in mice, and can also cure extensive established lung metastatic disease. We also show that the mechanism of protection involves antibody-mediated blockade of ErbB-2 function, independent of Fc receptors. We conclude that a vaccine inducing antibodies to a functional oncogenic receptor could have tremendous therapeutic potential against cancers overexpressing such molecules. [Cancer Res 2008;68(6):1979–87]
SOX9 Is Expressed in Human Fetal Prostate Epithelium and Enhances Prostate Cancer Invasion
Authors: Wang Hongyun , Leav Irwin , Ibaragi Soichiro , Wegner Michael , Hu Guo-fu , Lu Michael L. , Balk Steven P. , Yuan Xin 
Published: March 2008

Abstract
SOX9 is a transcription factor that plays a critical role in the development of multiple tissues. We previously reported that SOX9 in normal human adult prostate was restricted to basal epithelium. SOX9 was also expressed in a subset of prostate cancer (PCa) cells and was increased in relapsed hormone-refractory PCa. Moreover, SOX9 expression in PCa cell lines enhanced tumor cell proliferation and was β-catenin regulated. Here we report additional in vivo results showing that SOX9 is highly expressed during fetal prostate development by epithelial cells expanding into the mesenchyme, suggesting it may contribute to invasive growth in PCa. Indeed, SOX9 overexpression in LNCaP PCa xenografts enhanced growth, angiogenesis, and invasion. Conversely, short hairpin RNA–mediated SOX9 suppression inhibited the growth of CWR22Rv1 PCa xenografts. These results support important functions of SOX9 in both the development and maintenance of normal prostate, and indicate that these functions contribute to PCa tumor growth and invasion. [Cancer Res 2008;68(6):1625–30]
Diphenyl Difluoroketone: A Curcumin Derivative with Potent In vivo Anticancer Activity
Authors: Subramaniam Dharmalingam , May Randal , Sureban Sripathi M. , Lee Katherine B. , George Robert , Kuppusamy Periannan , Ramanujam Rama P. , Hideg Kalman , Dieckgraefe Brian K. , Houchen Courtney W. , Anant Shrikant 
Published: March 2008

Abstract
Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was reported to inhibit proliferation of a variety of cancer cells in vitro. However, the efficacy and in vivo mechanism of action of EF24 in gastrointestinal cancer cells have not been investigated. Here, we assessed the in vivo therapeutic effects of EF24 on colon cancer cells. Using hexosaminidase assay, we determined that EF24 inhibits proliferation of HCT-116 and HT-29 colon and AGS gastric adenocarcinoma cells but not of mouse embryo fibroblasts. Furthermore, the cancer cells showed increased levels of activated caspase-3 and increased Bax to Bcl-2 and Bax to Bcl-xL ratios, suggesting that the cells were undergoing apoptosis. At the same time, cell cycle analysis showed that there was an increased number of cells in the G2-M phase. To determine the effects of EF24 in vivo, HCT-116 colon cancer xenografts were established in nude mice and EF24 was given i.p. EF24 significantly suppressed the growth of colon cancer tumor xenografts. Immunostaining for CD31 showed that there was a lower number of microvessels in the EF24-treated animals coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA and protein expression. Western blot analyses also showed decreased AKT and extracellular signal-regulated kinase activation in the tumors. Taken together, these data suggest that the novel curcumin-related compound EF24 is a potent antitumor agent that induces caspase-mediated apoptosis during mitosis and has significant therapeutic potential for gastrointestinal cancers. [Cancer Res 2008;68(6):1962–9]
GM1 and Tumor Necrosis Factor-α, Overexpressed in Renal Cell Carcinoma, Synergize to Induce T-Cell Apoptosis
Authors: Das Tanya , Sa Gaurisankar , Hilston Cynthia , Kudo Daisuke , Rayman Patricia , Biswas Kaushik , Molto Luis , Bukowski Ronald , Rini Brian , Finke James H. , Tannenbaum Charles 
Published: March 2008

AbstractThe ability to induce T-cell apoptosis is one mechanism by which tumors evade the immune system, although the molecules involved remain controversial. We found that renal cell carcinoma (RCC)–induced T-cell apoptosis was inhibited by &gt;50% when cocultures were performed with ganglioside-depleted tumor cells, caspase-8–negative lymphocytes, or anti–tumor necrosis factor-α (TNFα) antibodies, suggesting that tumor gangliosides synergize with signals delivered through TNFα death receptors to mediate T-cell killing. The synergy between tumor-derived TNFα and the RCC-overexpressed ganglioside GM1 for killing resting T cells is corroborated by studies using purified GM1 and rTNFα, which indicate that a 48-hour pretreatment with the ganglioside optimally sensitizes the lymphocytes to a TNFα-induced apoptotic death. However, activated T cells, which synthesize TNFα themselves, can be killed by exogenous GM1 alone. RelA-overexpressing lymphocytes are protected from GM1 plus TNFα-mediated apoptosis, a finding consistent with our previous studies indicating that gangliosides inhibit nuclear factor-κB activation. These results are clinically relevant because, similar to T-cells cocultured with GM1-overexpressing RCC lines, T cells isolated from the peripheral blood of patients with metastatic RCC are also heavily coated with that tumor-shed ganglioside. This population of patient cells, unlike T cells isolated from normal donors, is highly susceptible to apoptosis induced by rTNFα or by metastatic patient sera, which contain elevated levels of the cytokine. This report thus extends our previous studies by demonstrating that tumor-derived TNFα enhances RCC apoptogenicity not only by inducing ganglioside synthesis but also by initiating receptor-dependent apoptosis in T cells in which the nuclear factor-κB activation pathway has been inhibited by GM1. [Cancer Res 2008;68(6):2014–23]
Silibinin Inhibits Colorectal Cancer Growth by Inhibiting Tumor Cell Proliferation and Angiogenesis
Authors: Singh Rana P. , Gu Mallikarjuna , Agarwal Rajesh 
Published: March 2008

Abstract
Herein, for the first time, we investigated in vivo efficacy and associated molecular biomarkers and mechanisms of a chemopreventive agent, silibinin, against human colorectal carcinoma (CRC) HT29 xenograft growth. Nude mice were implanted with HT29 cells and fed with vehicle (carboxymethyl cellulose or phosphatidylcholine) or 200 mg/kg/d dose of silibinin or 100 and 200 mg/kg/d doses of silybin-phytosome (5 days per week) for 32 days. Silibinin inhibited tumor growth that accounted for 48% (P = 0.002) decrease in tumor volume and 42% (P = 0.012) decrease in tumor weight at the end of the experiment without any adverse health effect. A stronger antitumor efficacy was observed with silybin-phytosome preparation. Silibinin decreased proliferation index by 40% (P &lt; 0.001), increased apoptotic index by ∼2-fold (P = 0.001), and reduced microvessel density by 36% (P = 0.001) in tumors. Antiproliferative and proapoptotic effects of silibinin were associated with down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation as well as cyclin D1 expression. Antiangiogenic effect of silibinin was coupled with a strong decrease in inducible nitric oxide synthase (NOS) and NOS3, cyclooxygenase-1 (COX-1) and COX-2, and hypoxia-inducing factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). These findings suggest in vivo antitumor efficacy of silibinin against CRC involving its antiproliferative, proapoptotic, and antiangiogenic activities. The inhibition of ERK1/2 and Akt signaling may account for antiproliferative and proapoptotic effects, whereas down-regulation of NOS, COX, HIF-1α, and VEGF expression could lead to antiangiogenic effect of silibinin against CRC. Overall, potential use of silibinin against human CRC could be suggested. [Cancer Res 2008;68(6):2043–50]
Promoter Methylation of Genes in and around the Candidate Lung Cancer Susceptibility Locus6q23-25
Authors: Tessema Mathewos , Willink Randy , Do Kieu , Yu Yang Y. , Yu Wayne , Machida Emi O. , Brock Malcolm , Van Neste Leander , Stidley Christine A. , Baylin Stephen B. , Belinsky Steven A. 
Published: March 2008

AbstractChromosomal aberrations associated with lung cancer are frequently observed in the long arm of chromosome 6. A candidate susceptibility locus at 6q23-25 for lung cancer was recently identified; however, no tumor suppressor genes inactivated by mutation have been identified in this locus. Genetic, epigenetic, gene expression, and in silico screening approaches were used to select 43 genes located in 6q12-27 for characterization of methylation status. Twelve (28%) genes were methylated in at least one lung cancer cell line, and methylation of 8 genes was specific to lung cancer cell lines. Five of the 8 genes with the highest prevalence for methylation in cell lines (TCF21, SYNE1, AKAP12, IL20RA, and ACAT2) were examined in primary lung adenocarcinoma samples from smokers (n = 100) and never smokers (n = 75). The prevalence for methylation of these genes was 81%, 50%, 39%, 26%, and 14%, respectively, and did not differ by smoking status or age at diagnosis. Transcription of SYNE1, AKAP12, and IL20RA was completely silenced by hypermethylation and could be restored after treatment with 5-aza-2-deoxycytidine. Significant associations were found between methylation of SYNE1 and TCF21, SYNE1 and AKAP12, and AKAP12 and IL20RA, indicating a coordinated inactivation of these genes in tumors. A higher prevalence for methylation of these genes was not associated with early-onset lung cancer cases, most likely precluding their involvement in familial susceptibility to this disease. Together, our results indicate that frequent inactivation of multiple candidate tumor suppressor genes within chromosome 6q likely contributes to development of sporadic lung cancer. [Cancer Res 2008;68(6):1707–14]
Novel SN-38–Incorporated Polymeric Micelle, NK012, Strongly Suppresses Renal Cancer Progression
Authors: Sumitomo Makoto , Koizumi Fumiaki , Asano Takako , Horiguchi Akio , Ito Keiichi , Asano Tomohiko , Kakizoe Tadao , Hayakawa Masamichi , Matsumura Yasuhiro 
Published: March 2008

AbstractIt has been recently reported that NK012, a 7-ethyl-10-hydroxy-camptothecin (SN-38)–releasing nanodevice, markedly enhances the antitumor activity of SN-38, especially in hypervascular tumors through the enhanced permeability and retention effect. Renal cell carcinoma (RCC) is a typical hypervascular tumor with an irregular vascular architecture. We therefore investigated the antitumor activity of NK012 in a hypervascular tumor model from RCC. Immunohistochemical examination revealed that Renca tumors contained much more CD34-positive neovessels than SKRC-49 tumors. Compared with CPT-11, NK012 had significant antitumor activity against both bulky Renca and SKRC-49 tumors. Notably, NK012 eradicated rapid-growing Renca tumors in 6 of 10 mice, whereas it failed to eradicate SKRC-49 tumors. In the pulmonary metastasis treatment model, an enhanced and prolonged distribution of free SN-38 was observed in metastatic lung tissues but not in nonmetastatic lung tissues after NK012 administration. NK012 treatment resulted in a significant decrease in metastatic nodule number and was of benefit to survival. Our study shows the outstanding advantage of polymeric micelle-based drug carriers and suggests that NK012 would be effective in treating disseminated RCCs with irregular vascular architectures. [Cancer Res 2008;68(6):1631–5]