|Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2002: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2001: ¥7,500,000 (Direct Cost: ¥7,500,000)
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 explore the molecular mechanisms of peritoneal dissemination of ovarian cancer cells, based on the analysis of the microenvironment of disseminating cancer cells.
Analysis of pH, pO2 and pCO2 of malignant ascitic or ovarian tumor fluids disclosed hypoxic environment of ovarian cancer cells. In addition, immunohistochemical study on the expression and hypoxia-inducible factor-1 alpha (HIF-1 alpha) showed that HIF-1 alpha is localized in the nuclei of tumor cells at the periphery of papillary projection. These findings indicate that ovarian cancer cells are exposed to hypoxia at the initial step of peritoneal dissemination.
cDNA microarray analysis demonstrated that hypoxi
a down-regulates the expression of cell adhesion molecules, E-cadherin and beta-catenin, in ovarian cancer cells. In ovarian carcinoma tissues, the tumor cells positive for HIF-1 alpha tended to lose E-cadherin expression. Northern blot and Western blot analyses also showed that hypoxia attenuates the expression of E-cadherin in ovarian cancer cells, via up-regulation of SNAL, a transcriptional represser of E-cadherin. Therefore, it is likely that hypoxic microenvironment plays an important role in the attenuation of cell adhesion and transformation into "metastatic phenotype" of cancer cells.
Our study on the expression of ras-related GTPases Rho in epithelial ovarian tumors revealed that it was elevated in ovarian carcinomas compared with benign tumors. In addition, its expression at mRNA and protein levels 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 in vitro invasiveness of ovarian 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. These findings indicate that up-regulation of Rho is essential in the tumor progression of ovarian carcinoma, and will be a molecular target in the future therapy. Less