Oncogenic Regulation of Extracellular Vesicle Proteome and Heterogeneity

Abstract

Mutational and epigenetic driver events profoundly alter intercellular communication pathways in cancer. This effect includes deregulated release, molecular composition, and biological activity of extracellular vesicles (EVs), membranous cellular fragments ranging from a few microns to less than 100 nm in diameter and filled with bioactive molecular cargo (proteins, lipids, and nucleic acids). While EVs are usually classified on the basis of their physical properties and biogenetic mechanisms, recent analyses of their proteome suggest a larger than expected molecular diversity, a notion that is also supported by multicolour nano‐flow cytometry and other emerging technology platforms designed to analyze single EVs. Both protein composition and EV diversity are markedly altered by oncogenic transformation, epithelial to mesenchymal transition, and differentiation of cancer stem cells. Interestingly, only a subset of EVs released from mutant cells may carry oncogenic proteins (e.g., EGFRvIII), hence, these EVs are often referred to as “oncosomes”. Indeed, oncogenic transformation alters the repertoire of EV‐associated proteins, increases the presence of pro‐invasive cargo, and alters the composition of distinct EV populations. Molecular profiling of single EVs may reveal a more intricate effect of transforming events on the architecture of EV populations in cancer and shed new light on their biological role and diagnostic utility.

A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

“…EVs are nano-particles surrounded by lipid membranes, containing a variety of molecular cargos such as proteins, small and large RNAs, DNA, lipids, glycans, minerals, and metabolites that are thus secreted by cells [1][2][3][4][5]. Earlier studies have classified the range of EVs into exosomes (50-200 nm), ectosomes (100-1000 nm; also known as microvesicles) [6][7][8], and apoptotic bodies (1-10 µm) based on their mechanisms of generation and release, while additional types of EVs have been reported, consisting of oncosomes (oncogenic EVs) [9][10][11], large oncosomes (1-10 µm) [12,13], matrix vesicles [14][15][16], migrasomes (50 nm to 3 µm) [17,18], exopheres (~4 µm), exomeres (~35 nm), and bacterial outer membrane vesicles (OMV) [19,20] [4,21]. EVs are also classified by their size into small EVs (s-EVs; 30-500 nm) and large EVs (L-EVs; >1 µm).…”

Exosome Release of Drugs: Coupling with Epithelial-Mesenchymal Transition

“…EVs are nano-particles surrounded by lipid membranes, containing a variety of molecular cargos such as proteins, small and large RNAs, DNA, lipids, glycans, minerals, and metabolites that are thus secreted by cells [1][2][3][4][5]. Earlier studies have classified the range of EVs into exosomes (50-200 nm), ectosomes (100-1000 nm; also known as microvesicles) [6][7][8], and apoptotic bodies (1-10 μm) based on their mechanisms of generation and release, while additional types of EVs have been reported, consisting of oncosomes (oncogenic EVs) [9][10][11], large oncosomes (1-10 μm) [12,13], matrix vesicles [14][15][16], migrasomes (50 nm to 3 μm) [17,18], exopheres (~4 μm), exomeres (~35 nm), and bacterial outer membrane vesicles (OMV) [19,20] [4,21]. EVs are also classified by their size into small EVs (s-EVs; 30-500 nm) and large EVs (L-EVs; > 1 µm).…”

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

“…Authors have been urged to consider use of operational terms for EV subtypes that refer to physical characteristics of EVs, such as size; small EVs (sEV) and medium/large EVs (m/lEVs), with ranges defined, for example, < 200 nm (small) or > 200 nm (large and/or medium), respectively [29,36,37]. Additionally, according to the history of discoveries and characteristics of EVs, additional types of EVs have been reported consisting of oncosomes (named after oncogenic EVs) [38,39], large oncosomes (1-10 µm) [40], matrix vesicles [41], migrasomes [42], exopheres (≈4 µm), exomeres (≈35 nm), and bacterial outer membrane vesicles (OMV) [43]. These vesicles often play basic roles in discarding molecules unfavorable for cells [44], while also mediating intercellular communication by transferring their cargos to recipient cells or organs in local and/or distant tissues [45].…”