Abstract 1527: Hepatocyte growth factor modulates adhesion of ovarian cancer cells to the peritoneum mesothelium through p70 S6 kinase

Ovarian cancer has the highest mortality of all gynecological cancers. These deaths are mainly due to the highly metastatic characteristic with already widespread peritoneal dissemination and malignant ascites at the time of diagnosis. However the molecular mechanisms that regulate ovarian cancer progression are poorly understood. A key step in this process is the adhesion of ovarian cancer cells to the peritoneal mesothelium. Hepatocyte growth factor (HGF) is present at high concentrations in ovarian cancer ascitic fluid. We show here a role for HGF signaling in the regulation of the peritoneal adhesion of ovarian cancer cells. HGF increased binding of ovarian cancer cells to peritoneal extracellular matrix (ECM) proteins fibronectin and laminin and their receptors α5, α6, and β1 integrin expression. Blockade of HGF resulted in reduced attachment of ovarian cancer cells to these ECM proteins, with a concomitant reduction of α5, α6, and β1 integrin expression, confirming that the effect was HGF specific. Similarly, the peritoneal ECM adhesion could be reversed by neutralizing antibodies to α5, α6, and β1 integrin. The adhesive phenotype and integrin expression activated by HGF could be blocked by specific inhibition of p70 S6 kinase (p70S6K) using short hairpin RNA or small molecule inhibitor, suggesting that HGF transmits the signal through p70S6K. Importantly, it also inhibited adhesion to primary human peritoneal mesothelial cells. These results identify a potential novel mechanism for HGF-induced peritoneal adhesion, which is mediated through p70S6K through regulation of α5, α6, and β1 integrin (This work is supported by the Hong Kong Research Grants Council Grant HKU7599/05M to A.S.T.W.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1527. doi:10.1158/1538-7445.AM2011-1527