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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

卵巢癌是妇科恶性肿瘤死亡的主要原因。卵巢癌患者的不良预后与腹膜播散有关;腹膜播散是一种转移过程，其中癌细胞从原发肿瘤分离，附着在腹膜上，并在该部位重新生长。本研究旨在通过对卵巢癌细胞腹膜播散微环境的分析，探讨卵巢癌细胞腹膜播散的分子机制，通过对恶性腹水或卵巢肿瘤腹水pH、pO 2和pCO 2的分析，揭示卵巢癌细胞腹膜播散的低氧环境。此外，对表达和缺氧诱导因子-1 α（HIF-1 α）的免疫组化研究表明，HIF-1 α定位于乳头状突起周围的肿瘤细胞核中。这些结果表明，卵巢癌细胞在腹膜转移的初始阶段暴露于缺氧。 ...更多信息 a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-1 α阳性的肿瘤细胞倾向于失去E-cadherin表达。北方印迹和Western印迹分析也表明，缺氧通过上调E-cadherin的转录抑制因子SNAL而减弱卵巢癌细胞中E-cadherin的表达。因此，低氧微环境可能在减弱细胞粘附和癌细胞向“转移表型”转化中起重要作用。我们对卵巢上皮性肿瘤中ras相关GTP酶Rho表达的研究表明，与良性肿瘤相比，卵巢癌中ras相关GTP酶Rho的表达升高。此外，其在mRNA和蛋白质水平的表达在腹膜播散中显著高于原发病灶。通过用溶血磷脂酸（LPA）处理上调和激活Rho增加卵巢癌细胞的体外侵袭力，并且用Rho的特异性抑制剂C3外切酶处理逆转LPA处理的效果。使用裸鼠的离体模型显示腹膜传播在组成型表达Rho的卵巢癌细胞中更突出。这些结果表明，Rho的上调在卵巢癌的肿瘤进展中是必不可少的，并将成为未来治疗的分子靶点。少