Novel Hypoxia-Associated Markers of Chemoresistance in Ovarian Cancer
Lynda McEvoy, Sharon O'Toole, Cathy Spillane, Britta Stordal, Michael Gallagher, Cara Martin, Lucy Norris, Noreen Gleeson, Alo McGoldrick, Fiona Furlong, Amanda McCann, Orla Sheils, John O'Leary. Trinity College Dublin, Dublin, Ireland; University College Dublin, Dublin, Ireland
Background: Ovarian cancer is the fifth leading cause of cancer in women and has poor long-term survival, in part, due to chemoresistance. Tumour hypoxia is associated with chemoresistance in ovarian cancer. However, relatively little is known about the genes activated in ovarian cancer which cause chemoresistance due to hypoxia. This study aimed to firstly identify genes whose expression is associated with hypoxia-induced chemoresistance, and secondly select hypoxia-associated biomarkers and evaluate their expression in ovarian tumours.
Design: Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines were exposed to combinations of hypoxia and/or cisplatin as part of a matrix designed to reflect clinically relevant scenarios. RNA was extracted and interrogated on Affymetrix Human Gene arrays. Differential gene expression was analysed for cells exposed to hypoxia and/or treated with cisplatin. Potential markers of chemoresistance were selected for evaluation in a cohort of ovarian tumour samples by RT-PCR.
Results: A wide range of genes associated with chemoresistance were differentially expressed in cells exposed to hypoxia and/or cisplatin. Selected genes [ANGPTL4, HER3 and HIF-1α] were chosen for further validation in a cohort of ovarian tumour samples. High expression of ANGPTL4 trended towards reduced progression-free and overall survival. High expression of HER3 trended to increased progression-free but reduced overall survival, while high expression of HIF-1α trended towards reduced progression-free and increased overall survival.
Conclusions: In conclusion, this study has further characterized the relationship between hypoxia and chemoresistance in an ovarian cancer model. We have also identified many potential biomarkers of hypoxia and platinum resistance and provided initial validation of a subset of these markers in ovarian cancer tissues.
Category: Gynecologic & Obstetrics
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 189, Wednesday Morning