In the year 2004, epithelial ovarian cancer (HOC) is expected to be the 4th leading cancer type among cancer-related deaths in women in the United States. Due to its symptomless development and the lack of accurate animal models, EOC pathogenesis remains among the least understood of all major cancers. Alterations in signaling pathways mediated by p53, p16/Rb and HGF/c-met occur frequently and are reported to be associated with the poor clinical prognosis. However, their specific roles in EOC formation remain uncertain. Recently we have demonstrated that the ovarian surface epithelium (OSE) - selective inactivation of tumor suppressor p53 results in carcinogenesis, and that inactivation of the retinoblastoma (Rb) gene dramatically accelerates this process. In this model, neoplasms closely resemble the aggressive variant of human serous adenocarcinoma. Our preliminary results indicate that, in addition to its role in cell proliferation, apoptosis and genomic instability, the cooperation between defective p53 and Rb pathways predisposes OSE to expression of such advanced cancer traits as increased motility and invasion. These traits remain dormant until Hepatocyte Growth Factor (HGF), produced by accumulating stromal cells, activates c-met signaling. To test this hypothesis, we propose (1) to determine contributions of p53 and p16/Rb towards motility and invasion during epithelial ovarian carcinogenesis, and (2) to evaluate roles of HGF and c-met in EOC invasion and intraperitoneal spreading. These studies should advance our understanding of the EOC pathogenesis by demonstrating new biological mechanisms by which defective p53 and Rb pathways may additionally facilitate the course of neoplastic progression and by establishing the role of HGF/c-met signaling as a permissive event leading to invasion during the OSE carcinogenesis.
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