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

• 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

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。卵巢癌患者的预后不良与腹膜传播有关。一个转移过程，其中癌细胞从原发性肿瘤中脱离，附着在腹膜上，并在现场重新生长。这项研究的目的是基于对传播癌细胞的微环境的分析，探索卵巢癌细胞腹膜腹膜传播的分子机制。恶性肿瘤或卵巢肿瘤的pH，PO2和PCO2的分析揭示了卵巢癌细胞的低氧环境。此外，关于表达和缺氧诱导因子-1α（HIF-1α）的免疫组织化学研究表明，HIF-1αα位于乳头状投影外围的核细胞中。这些发现表明，在腹膜传播的第一步，卵巢癌细胞暴露于缺氧。CDNA微阵列分析表明，在卵巢癌细胞中，Hypoxi…更多的是一种低调的细胞粘附分子，E-钙粘蛋白和β-蛋白的表达。在卵巢癌组织中，HIF-1α呈阳性的肿瘤细胞倾向于失去E-钙粘蛋白的表达。 Northern印迹和Western印迹分析还表明，缺氧是通过上调E-Cadherin的转录反射剂SNAL的上调来减弱卵巢癌细胞中电子钙粘着蛋白的表达。因此，低氧微环境可能在细胞粘附和转化为癌细胞“转移表型”的衰减中起重要作用。我们关于上皮卵巢肿瘤中与RAS相关GTPases RHO表达的研究表明，与良性肿瘤相比，它在卵巢癌中升高。此外，在腹膜传播中其在mRNA和蛋白质水平上的表达明显高于原发性病变。通过用溶血杂种酸（LPA）治疗RHO的上调和激活增加了卵巢癌细胞的体外侵入性，并用RHO的特定抑制剂C3 Exoenzyme治疗逆转了LPA处理的作用。使用裸鼠的离体模型表明，腹膜传播在构成表达Rho的卵巢癌细胞中更为突出。这些发现表明，RHO的上调在卵巢癌的肿瘤进展中至关重要，并且将是将来治疗的分子靶标。较少的

项目成果

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