胃癌MSCs调节巨噬细胞极化促进胃癌发展的作用及机制研究

In our previous study, we have found that mesenchymal stem cells (MSCs) can induce macrophage polarization and have successfully isolated gastric cancer-derived MSCs (GC-MSCs) from human gastric cancer tissues. The role and mechanism of GC-MSCs in gastric cancer progression are unclear. This project is designed to investigate whether the prompting role of GC-MSCs in gastric cancer progression is through the regulation of macrophage polarization. The effect of GC-MSCs on the switch from M1 to M2 phenotype macrophages and the contribution of polarized macrophages by GC-MSCs to gastric cancer progression will be studied by using cell and molecular biology technologies. The key factors released by GC-MSCs that induce macrophage polarization will be screened by using Luminex assay and the related signaling pathways that mediate their effects will also be investigated. Depletion of the key factors or macrophages in vitro and in vivo will be performed to confirm that GC-MSCs prompt gastric cancer progression by regulating macrophage polarization. Moreover, the correlation between the number and location of GC-MSCs and M2 macrophages in gastric cancer tissues will be analyzed to evaluate the clinical significance of macrophage polarization by GC-MSCs in gastric cancer. The successful accomplishment of this study will reveal a new mechanism for the role of GC-MSCs in gastric cancer and provide new targets for the diagnosis and therapy of gastric cancer.

我们发现间质干细胞(MSCs)具有诱导巨噬细胞极化的作用，并成功从胃癌组织中分离获得了胃癌MSCs(GC-MSCs)。GC-MSCs在胃癌发展中的作用及机制值得研究。本研究旨在探讨GC-MSCs调节巨噬细胞极化促进胃癌发展的作用及机制。采用细胞与分子生物学技术研究GC-MSCs对巨噬细胞M1/M2亚型极化的作用，探讨GC-MSCs极化后的巨噬细胞对胃癌生长的影响。利用Luminex液态芯片法筛选GC-MSCs调节巨噬细胞极化的关键因子，并研究其影响的关键信号通路。结合体内外关键因子和巨噬细胞清除实验，证实巨噬细胞极化对GC-MSCs发挥促胃癌作用的影响。进一步分析胃癌组织中GC-MSCs与M2亚型巨噬细胞的数量与组织定位相关性，评价GC-MSCs调节巨噬细胞极化在胃癌发展中的意义。本研究将揭示GC-MSCs极化巨噬细胞促进胃癌发展的新机制，为胃癌诊断与治疗提供新的靶点和思路。

胃癌是我国最常见的恶性肿瘤之一，世界卫生组织最新统计表明胃癌的发病率和死亡率仍呈上升趋势。针对胃癌发生发展的研究备受我国学者关注。早期研究中我们发现间质干细胞(MSCs)具有诱导巨噬细胞极化的作用，并成功从胃癌组织中分离获得了胃癌MSCs (GC-MSCs)。然而，GC-MSCs在胃癌发展中的作用及机制值得研究。本研究旨在探讨GC-MSCs调节巨噬细胞极化促进胃癌发展的作用及机制。采用细胞与分子生物学技术研究GC-MSCs对巨噬细胞M1/M2亚型极化的作用，探讨GC-MSCs极化后的巨噬细胞对胃癌生长的影响。利用Luminex液态芯片法筛选GC-MSCs调节巨噬细胞极化的关键因子，并研究其影响的关键信号通路。结合体内外关键因子和巨噬细胞清除实验，证实巨噬细胞极化对GC-MSCs发挥促胃癌作用的影响。进一步分析胃癌组织中GC-MSCs与M2亚型巨噬细胞的数量与组织定位相关性，评价GC-MSCs调节巨噬细胞极化在胃癌发展中的意义。.我们的研究结果证实，GC-MSCs对胃癌细胞的增殖、迁移以及促血管生成能力均具有明显促进作用，且该作用与非恶性组织来源的GCN-MSCs或BM-MSCs相比更强。GC-MSCs分泌的IL-8细胞因子水平显著高于GCN-MSCs或BM-MSCs，结合IL-8中和抗体试验我们证实细胞因子IL-8是GC-MSCs发挥促胃癌效应的关键因子之一。体内裸鼠致瘤试验结果提示，单核/巨噬细胞参与了GC-MSCs促胃癌生长作用的发挥，且GC-MSCs共注射组裸鼠肿瘤组织中M2亚型巨噬细胞的浸润程度显著高于对照组。胃癌患者癌组织中M2亚型巨噬细胞相关蛋白的表达水平也明显高于癌旁组织。体外共培养试验研究证实，GC-MSCs可促进巨噬细胞由M1向M2亚型的极化。GC-MSCs极化后的巨噬细胞通过诱导胃癌细胞发生EMT而对胃癌细胞的迁移能力发挥显著促进作用。.综上所述，本项目研究成果首次证实了胃癌微环境中GC-MSCs具有调节巨噬细胞由M1向M2亚型转换的作用，揭示了GC-MSCs极化巨噬细胞促进胃癌发展的新机制，有望为胃癌诊断与治疗提供新的靶点与思路。