Abstract
Hypoxia is a common hallmark of solid tumors and is associated with aggressiveness, metastasis and poor outcome. Cancer cells under hypoxia undergo changes in metabolism and there is an intense crosstalk between cancer cells and cells from the tumor microenvironment. This crosstalk is facilitated by small extracellular vesicles (sEVs; diameter between 30 and 200 nm), including exosomes and microvesicles, which carry a cargo of proteins, mRNA, ncRNA and other biological molecules. Hypoxia is known to increase secretion of sEVs and has an impact on the composition of the cargo. This sEV-mediated crosstalk ultimately leads to various biological effects in the proximal tumor microenvironment but also at distant, future metastatic sites. In this review, we discuss the changes induced by hypoxia on sEV secretion and their cargo as well as their effects on the behavior and metabolism of cancer cells, the tumor microenvironment and metastatic events.
Highlights
Extracellular vesicles are defined as particles, which are delimited by a lipid bilayer and which cannot replicate [1]
Microvesicles biogenesis occurs by outward budding of the plasma membrane and exosome biogenesis takes place by inward budding of multivesicular bodies (MVB) with the plasma membrane and this fusion results in the formation of intraluminal vesicles (ILV), which are released into the extracellular medium [6]
Protein arginine methyltransferase 5 (PRMT5), which we have recently found to be enriched in hypoxic melanoma small extracellular vesicles (sEVs) [22], was shown to be involved in drug resistance against CDK4/6 inhibitors in melanoma [109]. miR-21, in sEVs from cancer-associated fibroblasts, can confer resistance to paclitaxel if transferred to ovarian cancer cells [110] and once again, hypoxia has been demonstrated to induce miR-21 expression [111], potentially increasing miR-21 levels in hypoxic sEVs
Summary
Extracellular vesicles are defined as particles, which are delimited by a lipid bilayer and which cannot replicate [1] They can be subdivided according to their size into small EVs (≤200 nm; sEVs) and medium/large EVs (> 200 nm; lEVs) [1]. Microvesicles biogenesis occurs by outward budding of the plasma membrane and exosome biogenesis takes place by inward budding of multivesicular bodies (MVB) with the plasma membrane and this fusion results in the formation of intraluminal vesicles (ILV), which are released into the extracellular medium [6] Both exosomes and microvesicles contain DNA, RNA, proteins, lipids and metabolites. Intra-tumoral hypoxia is caused by the lack of blood vessels and the fast growing rate of cancer cells, which adapt to this low tissue oxygenation by activating the hypoxia-inducible transcription factors (HIFs). Hypoxic sEVs’ Cargo and Its Role in Key Biological Processes Related to Cancer
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