Maarten P. Bebelman, Martine J. Smit, Michiel Pegtel, S. Rubina Bagliof
Exosomes are a group of vesicles created within endosomal chambers. Exosomes play a regulatory role in cell to cell communication. Exosomes can contribute to the progression of cancer by facilitating a link between stromal cells and tumors. Exosomes provide the hub network that connects tumors with external stimuli. Exosome biogenesis and cargo sorting is caused by multiple mechanisms.
Extracellular Vesicle Biogenesis
Exosomes are generated through the “inward budding of the limiting membrane of multivesicular bodies, leading to the generation of intraluminal vesicles.” After maturation, the multivesicular bodies fuse with the membrane and the intraluminal vesicles, now exosomes, are released into the extracellular space.
It is known that MVB biogenesis occurs through multiple channels; lipid raft microdomains and the sorting of cargo molecules (i.e the endosomal sorting complex required for transport), although more research is needed.
MVB Fate and Fusion with the Plasma Membrane
MVBs can either fuse with the plasma membrane and secrete exosomes or destroy their cargo by fusing with lysosomes. In cancer patients, MVBs tend to excrete higher levels of exosomes. A study done by Villarroya-Beltri suggests that the secretion of exosomes in cancer patients can be reduced by utilizing ISGylation of the ESCRT-1 component Tsg101 by encouraging fusion with lysosomes. The quality of the cellular environment also determines the fate of MVBs.
Deregulation of EV Release in Cancer
The release of microvesicles and exosomes can be controlled via autonomous cellular mechanisms, activated oncogenic signaling, and by degrading the cellular environment (i.e hypoxia).
Function of EVs in Cancer
Further research is needed to determine “whether the sorting of “modified” cargo into cancer EVs reflects the rapid turnover of abundant cancer cell components or a regulated process for intercellular communication.” Tumor angiogenesis is promoted by cancer EVs through the alteration of stromal cell behavior. Altering stromal cell behavior contributes to immunosuppression and the “acquisition of malignant traits by cancer cells.”
EVs in Pre-Metastatic Niche Formation
Cancer EVs are not just limited to the tumor microenvironment. They can enter into circulation and affect distant organ systems by creating favorable environmental conditions that encourage the growth of tumors.