Abstract 4367: Contribution of malignant thrombocytosis to ovarian cancer proliferation and resistance to chemotherapy-induced-apoptosis through Platelet Derived Growth Factor Receptor-Alpha (PDGFRA) signaling

Abstract

Abstract Background: Thrombocytosis at the time of ovarian cancer diagnosis is correlated with decreased interval to progression and decreased overall survival, but the mechanisms for these outcomes are poorly understood. We considered the possible role of Platelet-Derived Growth Factor (PDGF) signaling through PDGFRA as a mechanism for platelet-driven increases in tumor cell growth and progression. Methods: In vitro (co-culture experiments with multiple ovarian cancer cell lines and platelets) and in vivo (orthotopic mouse model of ovarian cancer) experiments were performed to assess the functional and biological effects of platelets on ovarian cancer with regard to invasion, proliferation, and apoptotic response to chemotherapy. In vitro assays queried whether PDGFRA may be implicated in the observed effects. Results: Co-culture assays of ovarian cancer cells with and without platelets showed increased ovarian cancer cell migration (p<0.05 for all cell lines) and proliferation (p<0.05 for all cell lines) in the presence of platelets. Co-culture assays including docetaxel showed ovarian cancer cells had a decreased apoptotic response in the presence of platelets (p<0.05 for all lines). Proliferative and anti-apoptotic effects did not require direct platelet-to-cell contact. Blocking PDGFRA using a monoclonal antibody and/or siRNA reversed, in part, the protective effects that platelets had in decreasing docetaxel-mediated apoptosis (p<0.05). In an orthotopic mouse model of ovarian cancer, platelet transfusions resulted in increased mean tumor weight (4.1g v 2.1g, p=0.03) and increased mean number of tumor nodules (62 v 20, p=0.004). These effects were abrogated by platelet pre-treatment with aspirin and by mouse treatment with aspirin. Immunohistochemistry of tumor specimens showed increased proliferation in the platelet transfused-mice compared to control (82.5% v 66.3%, p<0.001) and decreased apoptosis in transfused-mice compared to control (37.5% decrease, p=0.009). CD31 suggested greater blood vessel maturation in platelet-transfused mice; the ratio of lumen-containing to total vessels was greater in the platelet transfused mice (1.23 v 0.679, p=0.03). Immunofluorescence studies demonstrated platelet extravasation into tumor, confirming the potential for direct platelet-tumor cell interaction. Conclusions: Adverse cancer outcomes correlated to thrombocytosis are partially explained by PDGF-mediated taxane resistance in vitro. We confirmed in vivo that thrombocytosis contributes to increased aggressiveness of malignancy, suggesting that the clinical and mechanistic implications of malignant thrombocytosis warrant further study in order to identify clinically relevant biomarkers and therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4367. doi:1538-7445.AM2012-4367