Antiangiogenic drugs in ovarian cancer

Kumaran, G.; Jayson, Gordon C; Clamp, Andrew R.

doi:10.1038/sj.bjc.6604767

Cited by 82 publications

(55 citation statements)

References 61 publications

(52 reference statements)

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“…Bevacizumab has therapeutic activity in ovarian cancer also as single agent (41,42) and 2 large-phase III clinical trials (GOG-218 and ICON7) are undergoing to establish whether it improves efficacy of standard chemotherapy (43,44). Our findings are potentially important for several reasons: First, they identify both AMPK activation and the glycolytic phenotype of tumors as novel biomarkers of pathologic response to anti-VEGF therapy, although further work will be required to validate these concepts and to determine their predictive value in patients.…”

Section: Discussionmentioning

confidence: 99%

Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

et al. 2011

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VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regression in highly glycolytic tumors. In addition, we found that the central metabolic protein kinase AMP-activated protein kinase (AMPK)-a cellular sensor of ATP levels that supports cell viability in response to energy stress-was activated by anti-VEGF therapy in experimental tumors. AMPK-a2 attenuation increased glucose consumption, tumor cell sensitivity to glucose starvation, and tumor necrosis following anti-VEGF therapy. Taken together, our findings reveal functional links between the Warburg effect and the AMPK pathway with therapeutic responses to VEGF neutralization in tumor xenograft models. Cancer Res; 71(12); 4214-25. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

et al. 2011

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“…1 Most cases present at an advanced stage and have a poor outcome, so efforts to detect ovarian cancer at an early stage would have a significant impact on the prognosis of ovarian cancers. Ovarian carcinogenesis has been evaluated at the molecular level and some candidate genes, such as p53, 2 PTEN, 3 and BRCA, 4 have been proposed to have roles in oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

Expression pattern of the class I homeobox genes in ovarian carcinoma

et al. 2010

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Objective: Although some sporadic reports reveal the link between the homeobox (HOX) genes and ovarian carcinoma, there is no comprehensive analysis of the expression pattern of the class I homeobox genes in ovarian carcinoma that determines the candidate genes involved in ovarian carcinogenesis. Methods: The different patterns of expression of 36 HOX genes were analyzed, including 4 ovarian cancer cell lines and 4 normal ovarian tissues. Using a reverse transcription-polymerase chain reaction (RT-PCR) and quantification analysis, the specific gene that showed a significantly higher expression in ovarian cancer cell lines than in normal ovaries was selected, and western blot analysis was performed adding 7 ovarian cancer tissue specimens. Finally, immunohistochemical and immunocytochemical analyses were performed to compare the pattern of expression of the specific HOX gene between ovarian cancer tissue and normal ovaries. Results: Among 36 genes, 11 genes had a different level of mRNA expression between the cancer cell lines and the normal ovarian tissues. Of the 11 genes, only HOXB4 had a significantly higher level of expression in ovarian cancer cell lines than in normal ovaries (p=0.029). Based on western blot, immunohistochemical, and immunocytochemical analyses, HOXB4 was expressed exclusively in the ovarian cancer cell lines or cancer tissue specimens, but not in the normal ovaries. Conclusion:We suggest HOXB4 may be a novel candidate gene involved in ovarian carcinogenesis.

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“…Ovarian cancer is the sixth most commonly diagnosed cancer (Permuth-Wey and Sellers, 2009) and the fourth most common cause of cancer death among women in the world (Kumaran et al, 2009). There are three major types of human ovarian cancers: epithelial, stromal and germ cell.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance

Cui

et al. 2011

Journal of Cell Science

113

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MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in gene regulation. We have previously reported that activin receptor-like kinase 7 (ALK7) and its ligand, Nodal, induce apoptosis in human epithelial ovarian cancer cells. In this study, we examined the regulation of ALK7 by miRNAs and demonstrate that miR-376c targets ALK7. Ectopic expression of miR-376c significantly increased cell proliferation and survival, enhanced spheroid formation and blocked Nodal-induced apoptosis. Interestingly, overexpression of miR-376c blocked cisplatin-induced cell death, whereas anti-miR-376c enhanced the effect of cisplatin. These effects of miR-376c were partially compensated by the overexpression of ALK7. Moreover, in serous carcinoma samples taken from ovarian cancer patients who responded well to chemotherapy, strong ALK7 staining and low miR-376c expression was detected. By contrast, ALK7 expression was weak and miR-376c levels were high in samples from patients who responded poorly to chemotherapy. Finally, treatment with cisplatin led to an increase in expression of mRNA encoding Nodal and ALK7 but a decrease in miR-376c levels. Taken together, these results demonstrate that the Nodal–ALK7 pathway is involved in cisplatin-induced cell death in ovarian cancer cells and that miR-376c enhances proliferation, survival and chemoresistance by targeting, at least in part, ALK7.

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Antiangiogenic drugs in ovarian cancer

Cited by 82 publications

References 61 publications

Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

Expression pattern of the class I homeobox genes in ovarian carcinoma

MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance

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