Hypoxia in tumor microenvironment regulates exosome biogenesis: Molecular mechanisms and translational opportunities

Hypoxia is a key feature of solid tumors, associated with disease aggressiveness and poor outcome. Besides undergoing broad intracellular molecular and metabolic adaptations, hypoxic tumor cells extensively communicate with their microenvironment to concoct conditions favorable for their survival, growth and metastatic spread. This mode of communication is through diverse secretory factors including exosomes (extracellular vesicles of endosomal origin and similar to 30-150 nm in diameter) which could carry package of molecular information including proteins, nucleic acids, lipids, and metabolites wrapped in lipid bilayer. Numerous studies have concluded that hypoxia promotes exosomes secretion by cancer cells. Moreover, exosomal cargo is considerably altered under hypoxia, dictating tumor cells communication with its local and distant microenvironment. In this review, we have summarized the effects of hypoxia on exosomes (Exo(Hypoxic)) secretion and cargo sorting (miRNAs, proteins, lipids and metabolites) as well as their biological effects in local and distant microenvironment. We have described the key molecular mechanisms (e.g. HIF-1 alpha, ceramides, RAB GTPases, tetraspanins, oxidative stress etc) involved in the production of Exo(Hypoxic). Lastly, we have highlighted the potential usefulness of Exo(Hypoxic) in cancer prognosis as well as therapeutic opportunities in targeting Exo(Hypoxic).