Abstract 1272: Apelin/Apj pathway for targeting ovarian tumor microenvironment

Abstract

Abstract Introduction: Ovarian cancer generates unique tumor microenvironment (TME) that promotes and enhances tumor progression and metastasis. Current therapy option for modulating ovarian TME is antiangiogenic therapy but its clinical benefit is limited; thus, alternative drug targets are needed for therapeutic durability. Apelin and its cognate receptor APJ is known to have roles in glucose metabolism, cardiovascular functions, and angiogenesis. We found that apelin/APJ are highly overexpressed in human ovarian tumors, but their functional role is unclear. We also found a significant upregulation of apelin/APJ in tumors that progressed after antiangiogenic therapy in preclinical ovarian cancer models. Our objective is to determine the functional roles and mechanisms of apelin/APJ pathway on promoting ovarian tumor angiogenesis and progression. Methods: We examined autocrine and paracrine functions of apelin/APJ signaling on cell proliferation, migration, and tube formation using human ovarian cancer cells (SKOV3Apln and SKOV3Apj) and endothelial cells (HUVECApj). Phosphoproteome array was performed to evaluate the apelin/APJ downstream signaling. We characterized the effect of apelin or APJ overexpression on tumor development and response to VEGFR inhibitor in vivo. To confirm the clinical relevance of apelin/APJ in ovarian TME, we measured soluble apelin levels in patients’ ascites and APJ expressions in human ovarian tumors using an immunohistochemistry. Results: Apelin (10-100 ng/ml) induced mitogenic and chemoattractant effects on both cancer and endothelial cells. These effects were more prominent under hypoxic condition, reflecting the significance of apelin/APJ axis in TME. The aplein-mediated proliferative and migratory effects were inhibited by a pharmacological APJ inhibitor (ML-221) in a dose-dependent manner. High APJ expression resulted in enhanced pro-angiogenic activity in HUVEC. Overexpression of apelin/APJ also led to reduced response to antiangiogenic treatment in both HUVEC and cancer cells. Apelin signaling induces phosphorylation of AKT, STAT, CREB, PRAS 40, and AMPKα2 in SKOV3 cells. Our xenograft study indicates APJ-overexpressing tumors showed reduced response to sorafenib treatment compared to those control tumors. We found that APJ is mainly expressed in tumors and some extent in stromal component of human ovarian tumors. The median soluble apelin levels in ascites were 187 pg/ml (6.3 - 4,000 pg/ml). Conclusions: Our results suggest that apelin/APJ may play an important role in promoting angiogenesis and progression in ovarian cancer and serve as an attractive pathway targeting ovarian TME. Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Samrita Dogra, Jihee Ha, Sukyung Woo. Apelin/Apj pathway for targeting ovarian tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1272.