568

Malignant ascites is a major cause of morbidity and mortality in ovarian cancer patients. It functions as a rich permissive microenvironment that represents the reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. We have recently reported the role of exogenous matricellular protein SPARC (secreted protein acidic and rich in cysteine) as a negative regulator of ID8 mouse ovarian cancer cell adhesion, growth, and survival in vitro. Employing a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP-/- mice, an inhibitory role for host SPARC was implicated through downregulation of tumor vascular endothelial growth factor (VEGF), VEGF receptors, and gelatinase matrix metalloproteinases (MMPs). Herein, we investigated the underlying molecular mechanisms of the interplay between host SPARC and the pro-survival/pro-metastasis factors. We found that the pronounced pro-invasive and pro-survival effects of SP-/- ascitic fluid were mediated by significantly high levels of VEGF and interleukin (IL)-6, major players implicated in the support of ovarian tumor growth and metastasis. In vitro, VEGF-induced ID8 invasion was dependent on binding to its cognate receptors (VEGFR1 and VEGFR2) and was mediated through MMP-2 and MMP-9. Augmented levels of VEGF in SP-/- ascites also accounted for increased ID8 invasiveness in vitro mainly through activation of αvvβ3, αvβ5) and β1 integrins. In agreement with these findings, ID8 cells stably overexpressing VEGF displayed levels of adhesion to and invasion of coated matrices comparable to that of ID8 cells treated with integrin-specific activators. Furthermore, presence of host SPARC significantly suppressed their tumorigenecity in vivo. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through downregulation of VEGF-VEGFR-MMP axis in general and antagonization of the bioactivity of VEGF and IL-6 in particular.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA