Extracellular vesicles as emerging intercellular communicasomes

Abstract

All living cells release extracellular vesicles having pleiotropic functions in intercellular communication. Mammalian extracellular vesicles, also known as exosomes and microvesicles, are spherical bilayered proteolipids composed of various bioactive molecules, including RNAs, DNAs, proteins, and lipids. Extracellular vesicles directly and indirectly control a diverse range of biological processes by transferring membrane proteins, signaling molecules, mRNAs, and miRNAs, and activating receptors of recipient cells. The active interaction of extracellular vesicles with other cells regulates various physiological and pathological conditions, including cancer, infectious diseases, and neurodegenerative disorders. Recent developments in high-throughput proteomics, transcriptomics, and lipidomics tools have provided ample data on the common and specific components of various types of extracellular vesicles. These studies may contribute to the understanding of the molecular mechanism involved in vesicular cargo sorting and the biogenesis of extracellular vesicles, and, further, to the identification of disease-specific biomarkers. This review focuses on the components, functions, and therapeutic and diagnostic potential of extracellular vesicles under various pathophysiological conditions.

Fig. 1.. Intercellular communication via extracellular vesicles. EVs are lipid-bilayered vesicles of 30-2,000 nm in diameter. Mammalian EVs are classified into exosomes and microvesicles, based on their biogenesis. Exosomes and microvesicles are generated by the fusion of multivesicular bodies with the plasma membrane and budding from the plasma membrane, respectively. EVs are intercellular communicasomes, harboring diverse bioactive materials, including RNAs, DNAs, proteins, and lipids. EVs regulate a diverse range of pathophysiological functions by activating receptors or transferring membrane proteins, signaling molecules, mRNAs, and miRNAs. These EVs can interact with recipient cells by ligand-receptor interactions, fusion, and internalization via receptor-mediated endocytosis or macropinocytosis.

Fig. 2.. Multiple functions of extracellular vesicles in the tumor microenvironment. The tumor microenvironment consists of a diverse range of cells including cancer cells, endothelial cells, fibroblasts, macrophages/monocytes, and immune cells. This heterogeneous population of cells secretes EVs into the tumor microenvironment. These EVs make an environment favorable for tumor progression. Cancer cell-derived EVs promote angiogenesis by modulating endothelial cell proliferation, migration, and invasion directly. Also, these EVs stimulate angiogenesis by activating macrophages to secrete proangiogenic factors and by promoting the induction of fibroblast differentiation into myofibroblasts. Moreover, cancer cell-derived EVs suppress immune responses by promoting the differentiation of monocytes into myeloid-derived suppressor cells and by inducing apoptosis of cytotoxic T lymphocytes.