Effect of estradiol on the expression of angiogenic factors in epithelial ovarian cancer

Introduction: Ovarian cancer presents a high angiogenesis (formation of new blood vessels) regulated by pro-angiogenic factors, mainly vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). An association between endogenous levels of estrogen and increased risk of developing ovarian cancer has been reported. Estrogen action is mediated by the binding to its specific receptors (ERa and ERβ), altered ERa/ERβ ratio may constitute a marker of ovarian carcinogenesis progression. Objective: To determine the effect of estradiol through ERa on the expression of NGF and VEGF in epithelial ovarian cancer (EOC). Methodology: Levels of phosphorylated estrogen receptor alpha (pERa) were evaluated in well, moderate and poorly differentiated EOC samples (EOC-I, EOC-II, EOC-III). Additionally, ovarian cancer explants were stimulated with NGF (0, 10 and 100 ng/ml) and ERa, ERβ and pERa levels were detected. Finally, human ovarian surface epithelial (HOSE) and epithelial ovarian cancer (A2780) cell lines were stimulated with estradiol, where NGF and VEGF protein levels were evaluated. Results: In tissues, ERs were detected being pERa levels significantly increased in EOC-III samples compared with EOC-I (p<0.05). Additionally, ovarian explants treated with NGF increased pERa levels meanwhile total ERa and ERβ levels did not change. Cell lines stimulated with estradiol revealed an increase of NGF and VEGF protein levels (p<0.05). Conclusions: Estradiol has a positive effect on pro-angiogenic factors such as NGF and VEGF expression in EOC, probably through the activation of ERa; generating a positive loop induced by NGF increasing pERa levels in epithelial ovarian cells.