Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization

Abstract

Hypoxia is a common feature of solid tumors. It is closely related to tumor progression. Exosomal microRNAs derived from cancers are considered to be mediators between cancer cells and the tumor microenvironment. In addition, the number of tumor-associated macrophages (TAMs) in the tumor microenvironment has also been demonstrated to correlate with tumor development. However, the relationship between tumor-secreted exosomes and TAM polarization under hypoxic conditions during tumor progression is not clear. Herein, we demonstrated that hypoxia induces the high expression of microRNA-940 (miR‑940) in exosomes derived from epithelial ovarian cancer (EOC). We also found that miR‑940 is highly expressed in exosomes isolated from ascites of EOC patients. Moreover, the overexpression of miR‑940 in macrophages delivered by exosomes stimulated M2 phenotype polarization, while the M2 subtype macrophages promoted EOC proliferation and migration. These results highlight the function of hypoxia in enhancing the high level of expression of miR‑940 in tumor exosomes taken up by macrophages. We also showed that the tumor-promoting function of miR‑940 is mediated by TAM polarization in EOC. These findings show that tumor-derived exosomal miR‑940 induced by hypoxia plays an important role in stimulating TAM polarization in the progression of EOC.

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

“…An increase in the miRNA‐940 level in exosomes isolated from hypoxia‐induced epithelial ovarian cancer (EOC) cells was observed by Chen et al They showed that exosomal miRNA‐940 increases the number of TAMs and induces M2 macrophage polarization, which were closely associated with ovarian cancer development and progression. Three years later, the same research team demonstrated that hypoxia increases exosomal levels of three miRNAs, including miRNA‐21–3p, miRNA‐125 b‐5p, and miRNA‐181 d‐5p, in human EOC cell lines (SKOV3 and HO‐8910).…”

The role of cancer-derived microRNAs in cancer immune escape

“…Abundant M2-like TAMs in the tumor microenvironment promote carcinogenesis by inducing angiogenesis, suppressing anti-cancer immune response, and antagonizing cancer cell apoptosis [143]. Epithelial ovarian cancer cells induced the polarization of TMAs toward M2-like phenotype via secreting exosomal miR-222-3p and miR-940 [127,128]. Besides, under hypoxic condition, epithelial ovarian cancer cell-secreted exosomes contained miRNAs such as miR-21-3p, miR-125b-5p, and miR-181d-5p, which enhanced the polarization of M2-like TAMs and promoted cancer growth [129].…”

“…Immunosuppressive [125] miR-24-3p NPC Immunosuppressive [126] miR-891a NPC Immunosuppressive [126] miR-106a-5p NPC Immunosuppressive [126] miR-20a-5p NPC Immunosuppressive [126] miR-1908 NPC Immunosuppressive [126] TAMs miR-222-3p EOC Immunosuppressive [127] miR-940 EOC Immunosuppressive [128] miR-21-3p EOC Immunosuppressive [129] miR-125b-5p EOC Immunosuppressive [129] miR-181d-5p EOC Immunosuppressive [129] miR-21 Head and neck cancer Immunosuppressive [130] miR-1246 Colon cancer Immunosuppressive [131] miR-16 Breast cancer Immunostimulatory [132] MDSCs miR-107 Gastric cancer Immunosuppressive [133] miR-21 OSCC Immunosuppressive [134] miR-21 Glioma Immunosuppressive [135] miR-10a Glioma Immunosuppressive [135] miR-29a Glioma Immunosuppressive [136] miR-92a Glioma Immunosuppressive [136] miR-155 CLL Immunosuppressive [137] CAFs miR-27a Gastric cancer Immunosuppressive [138] miR-1247-3p HCC Immunosuppressive [139] miR-21 HCC Immunosuppressive [140] NPC nasopharyngeal carcinoma, TAM tumor-associated macrophage, EOC epithelial ovarian cancer, MDSC myeloid-derived suppressor cell, OSCC oral squamous cell carcinoma, CLL chronic lymphocytic leukemia, CAF cancer-associated fibroblast, HCC hepatocellular carcinoma M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131].…”

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

“…This process caused macrophage polarization towards a TAM-like phenotype, which promoted the progression of EOC. Furthermore, exosome-derived miR-940 was released by hypoxic EOC and induced TAM polarization [153]. Another study showed that, under hypoxic conditions, exosomal miR-21-2p, miR-125b-5p, and miR-181d-5p were delivered to PMA-treated U937 cells and induced polarization towards TAMs in vitro and in vivo [154].…”