Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein

Background: 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. Methods: 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. Results: 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 alpha 2 chain (IL-13R alpha 2) molecules on the plasma membranes of cancer cells. Activation of IL-13R alpha 2 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. Conclusions: 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.