Potential Roles of Tumor Cell- and Stroma Cell-Derived Small Extracellular Vesicles in Promoting a Pro-Angiogenic Tumor Microenvironment

SIMPLE SUMMARY: In this review, we focus on the distinct functions of tumor-cell-derived small extracellular vesicles in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we focus on extracellular vesicles derived from non-cancer cells and their potential role in stimulating a pro-angiogenic tumor microenvironment. The article describes the biogenesis of small extracellular vesicles and refers to their proteomic cargo components that play a role in promoting angiogenesis. Moreover, we explain how small extracellular vesicles derived from tumors and non-cancer cells can interact with recipient cells and alter their functions. We particularly focus on phenotypical and functional changes in endothelial cells, macrophages, and neutrophils that result in proangiogenic signaling. ABSTRACT: Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. They are characterized by a distinct biogenesis and complex cargo composition, which reflects the cytosolic contents and cell-surface molecules of the parent cells. This cargo consists of proteins, nucleic acids, and lipids and is competent in inducing signaling cascades in recipient cells after surface interactions or in initiating the generation of a functional protein by delivering nucleic acids. Based on these characteristics, sEVs are now considered as important mediators of intercellular communication. One hallmark of sEVs is the promotion of angiogenesis. It was shown that sEVs interact with endothelial cells (ECs) and promote an angiogenic phenotype, ultimately leading to increased vascularization of solid tumors and disease progression. It was also shown that sEVs reprogram cells in the tumor microenvironment (TME) and act in a functionally cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from other cell types. In this review, we will focus on the distinct functions of tumor-cell-derived sEVs (TEX) in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we will focus on non-cancer stroma-cell-derived small extracellular vesicles and their potential role in stimulating a pro-angiogenic TME.