CCL5-CCR5介导的肾癌“干性”调控研究：基于间充质干细胞与肾癌“对话”机制

项目名称： CCL5-CCR5介导的肾癌“干性”调控研究：基于间充质干细胞与肾癌“对话”机制

项目编号： No.81502205

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 梁亮

作者单位： 西安交通大学

项目金额： 18万元

中文摘要： 肾细胞癌转移与复发是导致患者预后不良的主要原因。肿瘤干细胞特性的增加是导致肿瘤转移与复发的重要机制。当前对于肾细胞癌“干性”的调节机制尚不明确。既往研究多聚焦于肾细胞癌内源性信号通路的失调，对于“肿瘤微环境”诱发的信号与肿瘤细胞间的“对话”过程缺乏关注。骨髓间充质干细胞是存在于肿瘤微环境中重要的间质细胞。预实验发现肾细胞癌能够特异性招募骨髓间充质干细胞，通过与间充质细胞的交互性“对话”增加肿瘤细胞“干性”而促进肿瘤进展，同时伴有CCL5-CCR5信号的特异性激活。因此我们假设：CCL5-CCR5信号特异性介导肾细胞癌“干性”调节过程，其有可能成为进展期肾细胞癌治疗靶点。本研究拟通过临床标本研究明确异常激活CCL5-CCR5信号与肿瘤特异性招募骨髓间充质干细胞间的相关性，应用分子生物学、细胞学实验方法验证CCL5-CCR5信号通路介导的肾细胞癌与骨髓间充质干细胞间“对话”机制及潜在治疗价值。

中文关键词： 肾肿瘤；肿瘤微环境；肿瘤干细胞；骨髓间充质干细胞；CCL5

英文摘要： The metastatic and recurrent Renal Cell Carcinoma lead to an poor prognosis for RCC patients. The increase of stemness characteristic is one of the important mechanisms which cause tumor metastasis and recurrence. Currently, the potential regulatory mechanisms for stemness ability are still unclear. Previous studies mainly focused on the disorder by endogenous signaling pathway, few of which focused on the interaction between RCC and tumor microenvironment (TME). The tumor and the surrounding microenvironment are closely related and interact constantly by paracrine and endocrine. Bone marrow mesenchymal stem cells (BM-MSCs) is one of the most important stromal cells in tumor micro environment. BM-MSCs is one of the circulating immune cell located in the bone marrow which can be recruited into the tumor site specifically, and also the accumulating evidences showed the important role in promoting malignant tumor progression. In our study, we found that the circulating BM-MSCs can be recruited into renal tumor sites and increased the metastatic ability of RCC. We further revealed that the increased metastatic ability of RCC was due to the increased stem population in renal tumors. CCL5-CCR5 signal pathway was dominantly up-regulated in in vivo and in vitro experiments. In this study, we’d like to dissect the CCL5-CCR5 signal roles and potential mechanisms during the interaction process between RCC and BM-MSCs by molecular and cellular experiments. Hopefully we can find a new and more effective approach for mRCC treatment by CCL5-CCR5 signal blockage treatment.

英文关键词： renal cell carcinoma;tumor microenvironment;Cancer stem cell;BM-MSCs;CCL5