Development of a new molecular target therapy for ovarian carcinoma based on the analyses of mechanisms for its peritoneal dissemination

点击翻译按钮获取中文摘要

Ovarian carcinoma is the leading cause of gynecological cancer death. The poor prognosis for patients with ovarian cancer is related with peritoneal dissemination ; a metastatic process in which cancer cells detach from the primary tumor, attach to the peritoneum, and re-grow at the site. The objective of this study is to develop a new molecular target therapy, based on the analyses of the molecular mechanisms of peritoneal dissemination of ovarian cancer cells.In the metastatic process, since cancer cells become independent from the blood supply and exposed to hypoxia, we focused on the hypoxic environment and. Ovarian cancer cells in the tip of papillary projection actually expressed HIF-1 alpha, being associated with reduced expression of E-cadherin. In vitro experiment indicated that hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL that is a repressor of E-cadherin promotor, and also increases the invasive capacity. These findings suggest that hypoxia play … More s an important role in the dissemination of ovarian cancer cells in the primary lesion.In the metastaic sites, we focused on the small GTPase RhoA, that is the candidate of common pathway from various growth signals from the ascites. The expression of RhoA was significantly higher in the peritoneal dissemination than in the primary lesion. Up-regulation and activation of Rho by treatment with lysophospahtidic acid (LPA) increased the invasiveness of cancer cells, and treatment with C3 exoenzyme, a specific inhibitor of Rho, reversed the effect of LPA treatment. Ex vivo model using nude mice showed that peritoneal dissemination was more prominent in ovarian cancer cells expressing Rho constitutively. In addition, our preliminary study showed that oral administration of statins, potential inhibitor of Rho activation, suppressed the peritoneal dissemination of ovarian cancer cells. These findings indicate that RhoA is a good molecular target in the new therapy for peritoneal dissemination of ovarian carcinoma. Less