Nodal诱导黑色素瘤细胞内皮样转化在血管生成拟态形成中的作用及机制

项目名称： Nodal诱导黑色素瘤细胞内皮样转化在血管生成拟态形成中的作用及机制

项目编号： No.81201643

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 陈陆霞

作者单位： 天津医科大学

项目金额： 23万元

中文摘要： 葡萄膜黑色素瘤(UM)是成人眼内最常见的恶性肿瘤，易转移，死亡率高。UM中存在一种特殊的血液供应模式即血管生成拟态(VM)，它与肿瘤转移及预后不良密切相关，但其形成机制尚未阐明。资料表明，胚胎形成因子Nodal可诱导黑色素瘤细胞发生内皮样转化，内皮样转化是上皮间充质转化(EMT)的一种形式，对于转化后的细胞是否参与形成VM，国内外尚无报道。我们前期研究首次证实了EMT可能是VM形成的核心机制。推测Nodal诱导的肿瘤细胞内皮样转化可能是围成VM的细胞来源之一，参与VM形成。为证实这一假设，本研究将从人体标本-细胞系-动物模型三个层次，研究Nodal及其下游分子在VM形成中的作用，从分子层面探讨Nodal上调或下调对细胞内皮样转化和VM形成能力的影响及机制，并进行体内验证。本课题将从新的视角阐明VM形成机制，为肿瘤细胞分化的基础研究提供新的思路和切入点，为临床治疗提供新靶点。

中文关键词： 血管生成拟态；葡萄膜黑色素瘤；胚胎形成因子；上皮间充质转化；信号通路

英文摘要： Uveal melanoma (UM), with susceptibility to metastasis and high death rate, is the most common intraocular malignant tumor in adults. There exists in the UM a special type of blood supply, i.e. vascular mimicry (VM), which is closely associated with tumor metastasis and poor prognosis. However, the mechanisms of the VM formation in the UM remains elusive. Evidence has shown that embryonic morphogenic factor Nodal can induce the endotheliod transformation of melanoma cells, a type of epithelial-mesenchymal transition (EMT). It has not been reported whether the transformed cells are involved in the VM formation. Our preliminary studies proved for the first time that EMT is one of the pivotal mechanisms underlying VM formation. We therefore hypothesize that the UM cells transforming into endothelium through Nodal induction are one of the cell sources of VM formation. To test this hypothesis, we will study the role of Nodal and its downstream signaling molecules in VM formation at three levels, including human samples, cell lines and animal models. We will also investigate the effects of Nodal upregulation or downregulation on endothelium transformation and VM formation as well as their underlying mechanisms at the molecular level, and the results will be confirmed in vivo. The project will ascertain the mechanisms

英文关键词： vasculogenic mimicry；uveal melanoma；Nodal；EMT；signaling pathway