Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment
Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment
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DOI：
10.1038/s41388-018-0564-x
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发表时间：
2019-03-21
期刊：
影响因子：
8
通讯作者：
Tanaka, Masamitsu
中科院分区：
文献类型：
--
作者：
Umakoshi, Michinobu;Takahashi, So;Tanaka, Masamitsu
肿瘤来源的细胞外囊泡（TEVs）分泌到血液中，在远处器官中形成转移前生态位；然而，目前尚不清楚tev如何传递以及它们如何影响肿瘤微环境中的基质细胞。肿瘤相关巨噬细胞（TAMs）通过与癌细胞和其他基质细胞相互作用，在癌症进展中起着关键作用。在这里，我们报道了TAMs的一种新功能：TEV内容物的传递和传输。tev合并巨噬细胞（TEV-M Phi s）侵袭性增强，分布广泛。在与宿主基质细胞（腹膜间皮细胞（PMCs）、成纤维细胞和内皮细胞）接触后，TEV-MFs释放出含有tev的膜泡，这一过程依赖于M Phi s中caspase-3的局部激活。分散的泡被纳入基质细胞，导致癌症来源的RNA和蛋白质（如tgf - β、活化的Src、Wnt3和HIF1 α）的转移。含有癌源成分的TEV-M phi分泌泡有助于受体间质细胞的肌成纤维改变。在tev注射小鼠中，由M Phi s传递的tev深入胃实质，并将tev传递到胃表面的pmc；这一过程诱导pmc发生间皮-间质转变。pmc浸润胃壁，形成生态位，促进肿瘤侵袭。M s的损耗阻止了这些事件的发生。此外，TEV-M Phi s创造了促转移的生态位。综上所述，这些结果表明tam具有一种新的功能：通过增加ca样细胞的数量，将癌症来源的成分转移到周围的基质细胞，并诱导促肿瘤微环境。
Tumor-derived extracellular vesicles (TEVs) secreted into the blood create a pre-metastatic niche in distant organs; however, it is unclear how TEVs are delivered and how they affect stromal cells in the tumor microenvironment. Tumor-associated macrophages (TAMs) have pivotal roles in cancer progression by interacting with cancer cells and other stromal cells. Here, we report a novel function of TAMs: delivery and transmission of TEV contents. TEV-incorporating macrophages (TEV-M Phi s) showed increased invasiveness and were disseminated widely. Upon contact with host stromal cells (peritoneal mesothelial cells (PMCs), fibroblasts, and endothelial cells), TEV-MFs released membrane blebs containing TEVs, a process dependent upon localized activation of caspase-3 in M Phi s. Scattered blebs were incorporated into stromal cells, leading to transfer of cancer-derived RNA and proteins such as TGF-beta, activated Src, Wnt3, and HIF1 alpha. TEV-M Phi-secreted blebs containing cancer-derived components contributed to myofibroblastic changes in recipient stromal cells. TEVs delivered by M Phi s penetrated deep into the parenchyma of the stomach in TEV-injected mice, and transmitted TEVs to PMCs lining the stomach surface; this process induced PMCs to undergo mesothelial-mesenchymal transition. PMCs infiltrated the gastric wall and created a niche, thereby promoting tumor invasion. Depletion of M Phi s prevented these events. Moreover, TEV-M Phi s created a pro-metastatic niche. Taken together, these results suggest a novel function for TAMs: transfer of cancer-derived components to surrounding stromal cells and induction of a pro-tumor microenvironment via an increase in the number of CAF-like cells.