Abstract B13: Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: Implications for antiangiogenic therapy

Abstract

Abstract Ovarian cancer is a lethal gynecologic malignancy with poor survival, hence it would benefit from therapies that block key signaling pathways involved in tumor-stromal interactions and tumor vascularity. We previously showed that Protease Activated Receptor 1 (PAR1) is an important regulator of angiogenesis, ascites and metastasis in peritoneal mouse models of ovarian cancer. In this study we tested the hypothesis that matrix metalloprotease1 (MMP-1) activates PAR1 which stimulates angiogenesis and tumorigenesis in ovarian cancer through its paracrine control of the endothelial CXCR1/2 receptors. We demonstrated that MMP-1-PAR1 stimulation leads to a 2–5 fold increase in several angiogenic factors including IL-8 and GRO from ovarian cancer cells. These secreted factors then act on endothelial CXCR1/2 receptors to cause endothelial cell proliferation, tube formation and migration. A cell penetrating pepducin, PZ-206, that targets the third intracellular loop of CXCR1 and CXCR2 receptors (also known as X1/2pal-i3) can significantly inhibit both endothelial cell proliferation and tube formation. Avastin-the VEGF blocking antibody was unable to inhibit IL-8 and GRO- stimulated tube formation. To validate our in vitro observations we injected matrigel plugs containing MMP-1 stimulated/unstimulated ovarian cancer (OVCAR-4) conditioned media into the flanks of nude mice. After 7 days, the matrigel plugs were harvested and stained for CD31 and whole mount confocal microscopy was done in a blinded manner. Mice injected with MMP-1 stimulated, OVCAR-4 CM showed an 8 fold increase in blood vessel formation which was significantly inhibited by injecting mice with CXCR1/2 inhibitor PZ206 (5mg/kg/d) as compared with control pepducin or vehicle. These studies will help us validate novel therapeutic targets such as CXCR1/2 pepducins for ovarian cancer that block angiogenesis and tumor progression to improve survival in this lethal disease. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B13.