Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization.
Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization.
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DOI：
10.1038/s41467-018-06268-0
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发表时间：
2018-09-14
影响因子：
16.6
通讯作者：
Yang MH
中科院分区：
文献类型：
--
作者：
Lee CC;Lin JC;Hwang WL;Kuo YJ;Chen HK;Tai SK;Lin CC;Yang MH
癌细胞和肿瘤微环境（TME）之间的良好相互作用促进了转移性肿瘤的生长。由于原发性和转移性肿瘤之间的不同启动过程，我们研究了原发性和转移性癌症的肿瘤相关巨噬细胞（TAM）的差异。在这里，我们发现，M1和M2标记物的双重表达是从原发性肿瘤的TAM中注意到的，而M2标记物的主要表达显示在转移性TAM中。在转移部位，TAM分泌白细胞介素-35（IL-35）以通过激活JAK 2-STAT 6-GATA 3信号传导来促进转移性定殖，从而逆转癌细胞中的上皮-间充质转化（EMT）。在原发性肿瘤中，炎症诱导的EMT上调癌细胞中IL-35受体的亚基IL 12 R β2，以帮助癌细胞在转移期间对IL-35作出反应。巨噬细胞中IL-35的中和或IL-35的敲除减少了转移性定殖。这些结果表明原发性和转移性肿瘤的不同TME，并为拦截转移提供了潜在的靶点。肿瘤微环境在原发部位和转移部位之间变化。在这里，他们报告了来自转移部位的肿瘤相关巨噬细胞主要是M2型，并分泌IL-35通过激活JAK 2-STAT 6-GATA 3信号传导促进转移。
A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis. Tumor microenvironment varies between primary and metastatic sites. Here they report tumor-associated macrophages from metastatic sites to be predominantly M2 type, and secrete IL-35 to promote metastasis through activation of JAK2–STAT6–GATA3 signaling.
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