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

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.

Predictive Role of Tumor-Stroma Ratio for Survival of Patients With Non-Small Cell Lung Cancer: A Meta-Analysis

“…Compared to genetic or immune prognostic markers, TSR could be obtained by conventional pathological analysis with a microscope, which is simple, inexpensive, effective, and feasible in real-world clinical practice [ 35 ]. Moreover, treatments targeting tumour stroma and other components of tumor microenvironment may be effective and promising [ 36 , 37 ]. Once therapy targeting tumor stroma becomes critical, measuring of TSR may be helpful to identify patients with optimal therapy response in patients with NSCLC.…”

Differences of Angiogenesis Factors in Tumor and Diabetes Mellitus

“…As the long-term stimulation of diabetes itself, the activation of PKC and other factors, promote the synthesis of PDGF is promoted to, increases the level of PDGF in the retina and kidney of diabetic patients, further advance the formation of new blood vessels by stimulating intercellular adhesion molecule -1 (IGAM-1) and other ways, and aggravate microvascular-related lesions. The tumor microenvironment also contains abundant PDGF, possibly for the following reasons: TAMs 32,49,50,63 and CAFs 31,46 can secrete PDGF, and on the other hand, active HIF-1 can increase the release of PDGF under hypoxia conditions. 35 PDGF promotes tumor angiogenesis through its effects and co-action with other factors, 8 but overexpression of PDGF-B significantly inhibits tumor growth in vivo.…”

“…TAMs are a large family of macrophages 49 and are the most abundant population of tumor-infiltrating immune cells in TME. 29,49,63 M1 or M2 macrophages are induced by Th1 and Th2 cytokines, respectively, are the two main cell subtypes of TAMs. Moreover, the two effects are opposite: M1 macrophages are mainly involved in killing tumor cells, while M2 macrophages can promote angiogenesis.…”

The Role of Tumor-Derived Exosomes (TEX) in Shaping Anti-Tumor Immune Competence

“…Since the role of ADO as a contributor to tumor progression has been recognized in recent years, numerous pre-clinical and clinical studies utilizing pharmacologic inhibitors, siRNA or antibodies specific for the components of the adenosine pathway and antagonists of adenosine receptors have been conducted (reviewed in [ 40 , 41 , 42 ]). Pre-clinical studies in various in vitro and in vivo tumor models have shown efficacy and are currently entering the clinical arena [ 25 , 43 , 44 ].…”