The impact of hypoxia on extracellular vesicle secretome profile of cancer

Extracellular vesicles (EVs) are emerging as key mediators of cell-to-cell communications and signal transporters between tumor and stroma, and hypoxia is a critical characteristic of tumor microenvironment (TME) in solid cancers. Hypoxia stimulates tumor cells to generate and secrete more EVs, and the EVs shed from cancer transfer biological information to boost hypoxia and hypoxia inducible factor (HIF) functionality. Hypoxia alters EV secretome profile to carry pro-tumorigenic factors for promoting numerous tumor-related processes including increased cancer cell proliferation and survival, immune escape, aberrant angiogenesis, and invasion and metastasis. Exosomal hypoxia inducible factor (HIF)-1 alpha is an essential driver of epithelial-mesenchymal transition (EMT) and stemness profile in cancer. Hypoxic cancer-derived EVs are also contributed to therapy resistance. In fact, EVs are messengers of hypoxic tolerance in cancer, which enable adaptation of tumor cells to changes occurring within TME for their further resistance and metastasis. Tracing EVs shed from hypoxic tumor cells into plasma provide important information about the genomic signature of cancer. In this review, we aimed to discuss about key tumorigenic events promoted by inter-connections between hypoxia and EVs, mainly exosomes, secreted into tumor area focusing on key hallmarks of cancer.

Automated summary

Extracellular vesicles (EVs), particularly exosomes, play a crucial role in the communication and signal transmission between tumor cells and the tumor microenvironment (TME). Hypoxia, a characteristic of TME, stimulates tumor cells to release more EVs, which transfer biological information to promote hypoxia and hypoxia inducible factor (HIF) functionality. The EVs secreted under hypoxic conditions carry pro-tumorigenic factors that contribute to various tumor-related processes including cancer cell proliferation and survival, immune escape, angiogenesis, invasion, metastasis, and therapy resistance. This review focuses on the interplay between hypoxia and EVs, particularly exosomes, and their impact on key hallmarks of cancer.