Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer
Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer
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胃癌来源的间充质基质细胞触发M2巨噬细胞极化，促进胃癌转移和EMT
DOI：
10.1038/s41419-019-2131-y
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发表时间：
2019-12-04
影响因子：
9
通讯作者：
Zhao, Shaolin
中科院分区：
文献类型：
--
作者：
Li, Wei;Zhang, Xu;Zhao, Shaolin
肿瘤微环境中的驻留巨噬细胞在肿瘤进展中发挥双重作用。到目前为止，肿瘤内巨噬细胞产生的机制仍然是未知的。在本研究中，在小鼠异种移植模型中观察了巨噬细胞在胃癌源性间充质基质细胞（GC-MSCs）促肿瘤作用中的重要性。在胃癌组织中，证实了Ym-1、Fizz-1、iNOS-1和CCR-2的高表达水平以及iNOS的低表达水平，并且通过双重免疫荧光组织化学观察到GC-MSCs和肿瘤相关巨噬细胞（TAMs）的共定位。从胃癌组织中分离的TAM主要显示M2表型。在共培养体系中，GC-MSC对巨噬细胞M2极化的贡献通过体外GC-MSC致敏的巨噬细胞的M2相关蛋白表达、M2样免疫表型和细胞因子谱来证实。通过中和抗体阻断IL-6/IL-8显著减弱GC-MSC通过JAK 2/STAT 3信号通路对M2样巨噬细胞极化的促进作用。此外，GC-MSC-致敏的巨噬细胞促进了胃癌细胞的迁移和侵袭，GC-MSC-致敏的巨噬细胞处理显著增强了胃癌细胞的EMT过程。我们的研究表明，肿瘤促进GC-MSC有助于M2巨噬细胞极化胃癌壁龛内通过大量分泌IL-6和IL-8。这些GC-MSC-致敏的巨噬细胞随后可以通过胃癌细胞中的EMT促进来促进胃癌转移。
Resident macrophages in the tumor microenvironment exert a dual role in tumor progression. So far, the mechanism of intratumoral macrophage generation is still largely unknown. In the present study, the importance of macrophages in the pro-tumor role of gastric cancer-derived mesenchymal stromal cells (GC-MSCs) was observed in a mouse xenograft model with macrophage depletion. In gastric cancer tissues, high expression levels of Ym-1, Fizz-1, arginase-1, and CCR-2, as well as a low expression level of iNOS, were verified, and co-localization of GC-MSCs and tumor-associated macrophages (TAMs) was observed by dual immunofluorescence histochemistry. TAMs isolated from gastric cancer tissues predominantly displayed an M2 phenotype. In a co-culture system, the contribution of GC-MSCs to M2 polarization of macrophages was confirmed by the M2-related protein expression, M2-like immunophenotype and cytokine profile of GC-MSC-primed macrophages in vitro. Blockade of IL-6/IL-8 by neutralizing antibodies significantly attenuated the promoting effect of GC-MSCs on M2-like macrophage polarization via the JAK2/STAT3 signaling pathway. In addition, GC-MSC-primed macrophages promoted the migration and invasion of gastric cancer cells, and the process of EMT in gastric cancer cells was significantly enhanced by GC-MSC-primed macrophage treatment. Our study showed that tumor-promoting GC-MSCs contribute to M2 macrophage polarization within the gastric cancer niche through considerable secretion of IL-6 and IL-8. These GC-MSC-primed macrophages can subsequently prompt gastric cancer metastasis via EMT promotion in gastric cancer cells.