Abstract
Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. SIGNIFICANCE: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.
Highlights
Tumor-associated macrophages (TAM) are the major player and orchestrate various factors in tumor microenvironment to facilitate tumor progression [1,2,3,4]
Boyden chamber assay was performed and SW48 cells treated by conditioned medium (CM) of M2 macrophages explored an increased number in cell migration compared with the corresponding cells treated by FBS-free medium (Fig. 1C, left)
The communication between colon cancer cells and the tumoreducated macrophages reprograms macrophages to create a microenvironment for tumor growth; this microenvironment enables tumor cells to metastasize after accomplishing a series of biological steps [33]
Summary
Tumor-associated macrophages (TAM) are the major player and orchestrate various factors in tumor microenvironment to facilitate tumor progression [1,2,3,4]. Macrophages can be polarized to M1 or M2 macrophages. M1-polarized macrophages are activated by cytokines such as IFNg and produce proinflammatory and immunostimulatory cytokines TAMs are thought to more closely resemble M2-polarized macrophages, which are activated by Th2 cytokines It has been reported that TAMs can promote proliferation, invasion, and metastasis of tumor cells, stimulate tumor-related angiogenesis, and inhibit antitumor immune response, following with the progression of tumor [8,9,10,11]. With the unraveling of the relationship between TAMs and tumors, TAMs are being recognized as potential thera-
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