Molecular mechanisms of peritoneal dissemination of ovarian cancer cell, based on the analysis of its microenvironment

基于微环境分析的卵巢癌细胞腹腔播散的分子机制

基本信息

批准号：
13470349
负责人：
KONISHI Ikuo
金额：
$ 9.22万
依托单位：
SHINSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470349/
关键词：
ovarian cancer peritoneal dissemination microenvironment hypoxia E-cadherin HIF-1alpha Rho microarray 接着因子血管新生

项目摘要

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 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 … More 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

卵巢癌是妇科癌症死亡的主要原因，卵巢癌患者的不良预后与腹膜播散有关；在该过程中，癌细胞从原发肿瘤脱落，附着在腹膜上，并在该部位重新生长。本研究的目的是在分析癌细胞播散的微环境的基础上，探讨卵巢癌细胞腹腔播散的分子机制。恶性腹水或卵巢肿瘤液体的pO2和pCO2揭示了卵巢癌细胞的缺氧环境。此外，对缺氧诱导因子1α（HIF-1α）的表达和免疫组织化学研究表明，HIF-1α定位于卵巢癌细胞。这些发现表明，卵巢癌细胞在腹膜的初始阶段就暴露在缺氧环境中。 cDNA微阵列分析表明，缺氧会下调卵巢癌细胞中细胞粘附分子E-钙粘蛋白和β-连环蛋白的表达。在卵巢癌组织中，HIF-1α阳性的肿瘤细胞倾向于表达。 Northern blot 和 Western blot 分析还表明，缺氧会通过上调 E-cadherin 的表达来减弱卵巢癌细胞中 E-cadherin 的表达。 SNAL是E-钙粘蛋白的转录抑制因子，因此，缺氧微环境很可能在细胞粘附减弱和癌细胞向“转移表型”转化中发挥重要作用。我们对ras相关GTPase Rho表达的研究。在上皮性卵巢肿瘤中，与良性肿瘤相比，其在卵巢癌中的表达升高。此外，其在腹膜中的 mRNA 和蛋白质水平的表达显着升高。溶血磷脂酸 (LPA) 治疗上调和激活 Rho 增加了卵巢癌细胞的体外侵袭性，而 Rho 特异性抑制剂 C3 外切酶治疗则逆转了 LPA 治疗的效果。使用裸鼠的离体模型表明，在组成型表达 Rho 的卵巢癌细胞中，腹膜播散更为显着。这些发现表明 Rho 的上调至关重要。卵巢癌的肿瘤进展，并将成为未来治疗的分子靶点。