Novel Hypoxia-Associated Markers of Chemoresistance in Ovarian Cancer

Background:<br/>Ovarian cancer is the fifth leading cause of cancer in women and has poor<br/>long-term survival, in part, due to chemoresistance. Tumour hypoxia is associated with<br/>chemoresistance in ovarian cancer. However, relatively little is known about the genes<br/>activated in ovarian cancer which cause chemoresistance due to hypoxia. This study<br/>aimed to firstly identify genes whose expression is associated with hypoxia-induced<br/>chemoresistance, and secondly select hypoxia-associated biomarkers and evaluate their<br/>expression in ovarian tumours.<br/>Design:<br/>Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer<br/>cell lines were exposed to combinations of hypoxia and/or cisplatin as part of a matrix<br/>designed to reflect clinically relevant scenarios. RNA was extracted and interrogated<br/>on Affymetrix Human Gene arrays. Differential gene expression was analysed for cells<br/>exposed to hypoxia and/or treated with cisplatin. Potential markers of chemoresistance<br/>were selected for evaluation in a cohort of ovarian tumour samples by R<br/>T-PCR.<br/>Results:<br/>A wide range of genes associated with chemoresistance were differentially<br/>expressed in cells exposed to hypoxia and/or cisplatin. Selected genes [ANGPTL4,<br/>HER3 and HIF-1<br/>α<br/>] were chosen for further validation in a cohort of ovarian tumour<br/>samples. High expression of ANGPTL4 trended towards reduced progression-free and<br/>overall survival. High expression of HER3 trended to increased progression-free but<br/>reduced overall survival, while high expression of HIF-1<br/>α<br/>trended towards reduced<br/>progression-free and increased overall survival.<br/>Conclusions:<br/>In conclusion, this study has further characterized the relationship between<br/>hypoxia and chemoresistance in an ovarian cancer model. We have also identified many<br/>potential biomarkers of hypoxia and platinum resistance and provided initial validation<br/>of a subset of these markers in ovarian cancer tissues.