Mechanisms underlying chemotherapy-induced vascular proliferation in ovarian cancer

Ovarian cancer is a leading cause of gynecological cancer-related death in Canadian women. Ovarian cancer is managed through surgical cytoreduction and carboplatin-based chemotherapy. Unfortunately, most patients often relapse or have reduced responses to initial chemotherapy. The mechanisms behind carboplatin resistance are poorly understood. In pilot studies, our group has observed vascular proliferation in patient samples following carboplatin treatment. The effectiveness of modulating neovascularization in combination with carboplatin has also been demonstrated in two large Phase 3 trials. In this study, I explore the underlying mechanisms of chemotherapy-induced vascular proliferation and potentially, tumour cell survival. I hypothesize that carboplatin induces angiogenic factors in ovarian cancer cells leading to microvascular endothelial cell survival. To test my hypothesis, I screened for a variety of angiogenic factors in ovarian cancer cells and vascular endothelial cells following exposure to carboplatin. My results show that a number of angiogenic genes are upregulated in response to carboplatin exposure, including placental growth factor (PGF). Preclinical studies have shown that inhibition of PGF prevents tumour growth and metastasis. Therefore, I tested the effect of PGF and condition media prepared from ovarian cancer cells following carboplatin challenge on endothelial cell survival. My results show that PGF and ovarian cancer condition media facilitates endothelial cell survival. I also found that carboplatin may induce PGF expression in ovarian cancer cells through β-catenin activation. Findings from this study may help better understand the effects of carboplatin exposure on ovarian cancer. Furthermore, the results may provide additional targets to increase carboplatin sensitivity in ovarian cancer patients