间充质干细胞参与大分割放疗中肺癌微血管损伤修复的作用及机制研究

项目名称： 间充质干细胞参与大分割放疗中肺癌微血管损伤修复的作用及机制研究

项目编号： No.81201754

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： 孟茂斌

作者单位： 天津医科大学

项目金额： 23万元

中文摘要： 研究表明大分割放射治疗（HFRT）可动员体内的间充质干细胞（MSCs）"归巢"至肿瘤微血管损伤处，但"归巢"至肿瘤微血管损伤处MSCs的作用及调控机制国内外尚未见报道。结合国内外文献及既往工作基础，我们推测：当HFRT对肿瘤微血管内皮细胞造成损伤时，受HIF-1α-SDF-1α/CXCR4信号通路的调控，MSCs "归巢"至损伤微血管处，受Notch信号通路调控转分化为对血管内皮细胞起营养和保护作用的周细胞，对损伤微血管进行修复，抗拒HFRT对内皮细胞的杀伤效应从而影响放疗疗效。据此，本项目拟采用细胞共培养及荷瘤小鼠模型，分别从分子、细胞及整体动物三个水平，以MSCs参与HFRT肺癌微血管损伤修复中的作用为研究主线，对调控MSCs命运的关键环节特别是关键分子靶点及信号通路进行系统研究。通过本课题的开展，将为临床优化HFRT的治疗方案提供新思路、新靶点，具有重要的理论意义和应用前景。

中文关键词： 间充质干细胞；大分割放射治疗；肺癌微血管；损伤修复；周细胞

英文摘要： Previous studies demonstrated that Hypofractionated Radiotherapy (HFRT) mobilizes Mesenchymal Stem Cells (MSCs) homing to injury sites of tumor microvasculature, however, the function and regulatory mechanism of this homing has not been reported neither in China nor abroad. Based on literature and our previous studies, we presume that MSCs home to damaged tumor microvasculature after HFRT regulated by the HIF-1α-SDF-1α/CXCR4 pathway, and differentiate into pericytes to nourish and protect endothelial cells governed by the Notch signaling, which repair injuried tumor microvasculature, resist the killing effects of HFRT on endothelial cells, and thus promote tumor growth and radioresisitance. Therefore, this project will use cell co-culture and tumor-bearing mice model to investigate the key molecular target and signaling pathway regulating MSCs fate, focusing on lung cancer microvasculature injured repair after HFRT by MSCs at molecular, cellular as well as animal levels. The predicted outcome of this project will provide novel ideas and targets to optimize HFRT treatment strategy in clinical setting.

英文关键词： Mesenchymal Stem Cell；Hypofractionated Radiotherapy；Lung Cancer Microvasculature；Injured Repair；Pericyte