Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.

Recently, cancer has been considered to be a complex system that includes the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most common immune-related stromal cells in the TME, and communication between cancer cells and TAMs is crucial for the progression of epithelial ovarian cancer (EOC). In this study, we revealed that exosomes derived from EOC cells remodel macrophages to a tumor-promoted phenotype, namely TAMs. In addition, hypoxic microenvironments have been postulated to facilitate this process in the TME, and hypoxia-inducible factors (HIFs) play an important role in this process. We found that TAMs educated by hypoxic exosomes derived from EOC cells promote tumor proliferation and migration in a feedback loop. Based on microarray analysis of normoxic and hypoxic exosomes, we discovered that a panel of miRNAs was enriched in hypoxic exosomes. And these three highly expressed miRNAs were induced by hypoxia via HIFs. In this study, we revealed that under hypoxic conditions, EOC cell-derived exosomes deliver miRNAs to induce M2 macrophage polarization, which promotes EOC cell proliferation and migration. This study suggests that these exosomes and associated miRNAs might serve as targets for novel treatments or diagnostic biomarkers for EOC.