Exosomes in hypoxia-induced remodeling of the tumor microenvironment

Exosomes are structurally and functionally pleiotropic nano-sized (~30-150 nm in diameter) extracellular vesicles (EVs) with endosomal origin. These vesicles are secreted by almost all cells and play a significant role in intercellular communication and bio-waste disposal. To a great extent, exosomes represent biological "snapshot" of parent cells, and their cargos (protein, nucleotides, lipids, and metabolites) are loaded uniquely under different pathophysiological conditions. For example, most cancerous cells secrete a higher amount of exosomes loaded with distinct cargos under stressful low oxygen condition i.e. hypoxia, a key characteristic of solid tumors responsible for disease aggressiveness and poor survival. Exosomes secreted under hypoxia (Exo^Hypoxic) play a vital role in aiding cancer cells crosstalk with its microenvironment constituents to create conditions advantageous for cancer growth and metastatic spread. In this review article, we have highlighted the effects of Exo^Hypoxic on various tumor microenvironment components involved in angiogenesis, survival, proliferation, pre-metastatic niches preparation, immunomodulation, epithelial-to-mesenchymal transition, invasion, metastasis, and drug resistance. We have also described key Exo^Hypoxic cargos (miRNA, proteins, etc) and their targets in the receipt cells, responsible for various biological effects. Finally, we have emphasized the applicability of Exo^Hypoxic as a biomarker of tumor hypoxia and disease prognosis.