Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells

Abstract

BackgroundCisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). However, the resistance often occurs with the mechanisms being not well understood. Recently, emerging evidence indicates that tumor-associated macrophages (TAMs) play an important role in chemoresistance of cancer. As the important mediators in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins to be involved in tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate cisplatin resistance in gastric cancer.MethodsM2 polarized macrophages were obtained from mouse bone marrow or human PBMCs stimulated with IL-4 and IL-13. Exosomes isolated from M2 macrophages culture medium were characterized, and miRNA expression profiles of M2 derived exosomes (M2-exos) were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate M2-exos mediated crosstalk between TAMs and tumor cells. Moreover, the in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice.ResultsIn this study, we showed that M2 polarized macrophages promoted cisplatin (DDP) resistance in gastric cancer cells and exosomes derived from M2 macrophages (M2-exos) are involved in mediating the resistance to DDP. Using miRNA profiles assay, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and cell lysate isolated from M2 polarized macrophage. Functional studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway by down-regulation of PTEN.ConclusionsOur findings suggest that exosomal transfer of tumor-associated macrophages derived miR-21 confer DDP resistance in gastric cancer, and targeting exosome communication may be a promising new therapeutic strategy for gastric cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0528-y) contains supplementary material, which is available to authorized users.

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

“…49 Crosstalk between TAM and cancer cells is complex and involves exosomes, cytokines, and metabolites. [50][51][52] In the present study, we focused on the cytokine CCL2 secreted by macrophages and TA B L E 1 Univariate and multivariate analyses of clinicopathological features associated with PFS of patients with hormone receptor-positive breast cancer examined its role in the endocrine resistance of breast cancer cells. We found that CCL2 activates the PI3K/Akt/mTOR pathway, which is a classical endocrine resistance pathway.…”

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

“…Whereas much of the focus of the field has been on the secretion of soluble factors, there has been recent evidence that the secretion of exosomes could be another mechanism used by TAMs to induce therapeutic resistance in tumor cells. For instance, exosomal miR‐21 secreted by TAMs confers cisplatin resistance in gastric cancer cells by enhancing the activation of PI3K/AKT signaling pathway . Similarly, another study has shown that the exosomal miR‐155 transferred by TAMs to neuroblastoma tumor cells induces resistance to cisplatin by directly down‐regulating TERF1, a component of the shelterin complex and inhibitor of telomerase …”

Exosomes in cancer development and clinical applications

“…Presumably, it is believed that such change is to promote survival, proliferation, and drug resistance of cancer cells, in part as a result of increased expression of chemoresistance‐inducing factor, Snail . Moreover, exosomes from TAM diminish chemotherapy sensitivity of cancers as a result of miR‐21 activity . These studies suggested that exosomes derived from tumor microenvironments play an active and essential role in the regulation of cancer chemo‐ and/or radiation resistance.…”