Interstitial flow promotes macrophage polarization toward an M2 phenotype.
Interstitial flow promotes macrophage polarization toward an M2 phenotype.
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DOI：
10.1091/mbc.e18-03-0164
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发表时间：
2018-08-08
影响因子：
3.3
通讯作者：
Kamm RD
中科院分区：
文献类型：
--
作者：
Li R;Serrano JC;Xing H;Lee TA;Azizgolshani H;Zaman M;Kamm RD
肿瘤组织的特征是从肿瘤到周围间质的间质液体增多。肿瘤微环境中的巨噬细胞是肿瘤进展的关键因素。虽然肿瘤组织内的化学刺激可以改变巨噬细胞的行为，但机械刺激，特别是肿瘤微环境中间质液体的流动对巨噬细胞表型的影响尚未被探索。在这里，我们使用三维仿生模型揭示了巨噬细胞可以感知和响应肿瘤组织间质液体流动的病理生理水平(∼3微米/S)。具体地说，间质流(IF)通过整合素/Src介导的涉及STAT3/6的机械转导途径将巨噬细胞极化为M2样表型。与这种流动诱导的M2极化一致，IF处理的巨噬细胞迁移速度更快，促进癌细胞迁移的能力增强。此外，IF引导巨噬细胞逆流迁移。由于IF从肿瘤向周围间质组织散发，我们的结果提示IF不仅可以诱导巨噬细胞M2极化，而且可以将这些M2巨噬细胞招募到肿瘤肿块，从而促进癌细胞的侵袭和肿瘤的进展。综上所述，我们的研究表明，IF可能是肿瘤免疫环境的关键调节因子。
Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.