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

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.

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。

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。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。研究 结果显示：（1）确定大分割放疗或/和抗血管生成治疗均可重塑肺癌微血管并恢复其正常功能、显著改善肿瘤组织的乏氧水平；并证实重塑肺癌微血管的关键靶标为周细胞募集；（2）系统综述周细胞在不同肿瘤中的表达差异，确定选择合适的时机有效调控周细胞的表达水平，应重视监控大分割放疗及常规分割放疗模式下肿瘤微血管周细胞的动态变化或许可使肿瘤患者从中获益；（3）：确定大分割放疗募集骨髓中的间充质干细胞迁移至肿瘤间质，分化为周细胞；且证实间充质干细胞的迁移及分化受SDF-1α/CXCR4及PDGF-B/PDGFR-β信号通路调控，为有效调控周细胞的表达水平提供分子机制。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。