Tumor-derived exosomes polarize macrophages toward a proinflammatory phenotype via miR-183
Tumor-associated macrophages (TAMs) play a critical role in the tumor inflammatory microenvironment and facilitate tumor growth and metastasis. Most types of tumors aberrantly express microRNAs (miRNAs), which can be transferred between cells by exosomes and can regulate gene expression in recipient cells, but it remains unclear whether tumor-derived miRNAs are transferred by exosomes and regulate the TAM phenotype. We report that 4T1 breast-cancer-cell-derived exosomes enhanced TAM expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha, and that inhibition of 4T1-cell exosome secretion through shRNA-mediated Rab27a/b depletion repressed tumor growth and metastasis and markedly downregulated IL-1beta, IL-6, and TNF-alpha in a 4T1 breast-tumor model. Furthermore, miRNA-expression profiling revealed that 3 miRNAs (miR-100-5p, miR-183-5p, and miR-125b-1-3p) were considerably more abundant in 4T1-cell exosomes than in bone marrow-derived macrophages, indicating potential exosome-mediated transfer of the miRNAs, and, notably, miR-183-5p was found to be transferred from 4T1 cells to macrophages through exosomes. Moreover, PPP2CA was verified as a miR-183-5p target gene, and PPP2CA downregulation enhanced NF-kappa B signaling and promoted macrophage expression of IL-1beta, IL-6, and TNF-alpha. Lastly, when miR-183-5p was downregulated in exosomes through miR-183-5p-sponge expression in 4T1 cells, these 4T1-derived exosomes triggered diminished p65 phosphorylation and IL-1beta, IL-6, and TNF-alpha secretion, and the miRNA downregulation also led to repression of tumor growth and metastasis in the 4T1 breast-tumor model in vivo. Thus, miR-183-5p expressed in tumor cells was transferred to macrophages by exosomes and promoted macrophage inflammatory phenotype by inhibiting PPP2CA expression, which contributed to tumor progression in a breast-cancer model.