Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.
Department of Surgery, MacKay Memorial Hospital and MacKay Medical College, Taipei, Taiwan.
Nat Commun. 2018 Sep 14;9(1):3763. doi: 10.1038/s41467-018-06268-0.
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.
癌细胞与肿瘤微环境（TME）之间的有利相互作用促进了转移性肿瘤的生长。由于原发性肿瘤和转移性肿瘤之间存在明显的起始过程，我们研究了原发性和转移性肿瘤相关巨噬细胞（TAMs）之间的差异。在这里，我们表明原发性肿瘤中的 TAMs 表现出 M1 和 M2 标志物的双重表达，而转移性 TAMs 则表现出 M2 标志物的优势表达。在转移性部位，TAMs 分泌白细胞介素-35（IL-35），通过激活 JAK2-STAT6-GATA3 信号通路促进转移性定植，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 上调了癌细胞中 IL-35 受体的亚基 IL12Rβ2，以帮助它们在转移过程中对 IL-35 作出反应。中和 IL-35 或敲除巨噬细胞中的 IL-35 可减少转移性定植。这些结果表明原发性和转移性肿瘤的 TME 存在明显差异，并为阻断转移提供了潜在的靶点。
