Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein.
Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein.
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肿瘤招募的M2巨噬细胞通过M2巨噬细胞分泌的CHI3L1蛋白促进胃癌和乳腺癌转移
DOI：
10.1186/s13045-017-0408-0
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发表时间：
2017-02-01
影响因子：
28.5
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Chen Y;Zhang S;Wang Q;Zhang X
巨噬细胞是几种关键的免疫细胞类型之一，被认为与肿瘤发生有关。然而，巨噬细胞促进肿瘤进展的机制在很大程度上是未知的。用质谱分析M1和M2巨噬细胞差异分泌的蛋白质。我们进行了GST下拉试验，用于鉴定与几丁质酶3样蛋白1（CHI 3L 1）蛋白相互作用的细胞膜受体。使用小鼠模型来验证CHI 3L 1在体内癌症转移中的功能。进行蛋白磷酸化和基因表达以研究CHI 3L 1处理后癌细胞的信号通路激活。M2巨噬细胞分泌的CHI 3L 1在体内外促进胃癌和乳腺癌细胞的转移。CHI 3L 1蛋白通过与癌细胞质膜上的白细胞介素-13受体α2链（IL-13 R α2）分子相互作用而发挥功能。CHI 3L 1通过激活IL-13 R α2，激活丝裂原活化蛋白激酶信号通路，导致基质金属蛋白酶基因表达上调，促进肿瘤转移。本研究的结果表明，与健康供体相比，胃癌或乳腺癌患者血清中的CHI 3L 1蛋白水平显著升高。我们的研究揭示了巨噬细胞与癌症转移的一个新方面，并表明CHI 3L 1可能是患者转移性胃癌和乳腺癌的标志物。本文的在线版本（doi：10.1186/s13045-017-0408-0）包含补充材料，可供授权用户使用。
The macrophage, one of the several key immune cell types, is believed to be involved in tumorigenesis. However, the mechanism of macrophages promoting tumor progression is largely unknown. The differentially secreted proteins of M1 and M2 macrophages were analyzed by mass spectrometry. We performed GST pull-down assay for the identification of cell-membrane receptors that interact with chitinase 3-like protein 1 (CHI3L1) protein. The mouse model was used to validate the function of CHI3L1 in cancer metastasis in vivo. Protein phosphorylation and gene expression were performed to study the signaling pathway activation of cancer cells after CHI3L1 treatment. M2 macrophage-secreted CHI3L1 promoted the metastasis of gastric and breast cancer cells in vitro and in vivo. The CHI3L1 protein functioned by interacting with interleukin-13 receptor α2 chain (IL-13Rα2) molecules on the plasma membranes of cancer cells. Activation of IL-13Rα2 by CHI3L1 triggered the activation of the mitogen-activated protein kinase signaling pathway, leading to the upregulated expression of matrix metalloproteinase genes, which promoted tumor metastasis. The results of this study indicated that the level of CHI3L1 protein in the sera of patients with gastric or breast cancer was significantly elevated compared with those of healthy donors. Our study revealed a novel aspect of macrophages with respect to cancer metastasis and showed that CHI3L1 could be a marker of metastatic gastric and breast cancer in patients. The online version of this article (doi:10.1186/s13045-017-0408-0) contains supplementary material, which is available to authorized users.