Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin

Abstract

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.

Potential Role of Exercise Induced Extracellular Vesicles in Prostate Cancer Suppression

“…However, a few clinical exercise trials demonstrating elevation of skeletal muscle-induced EVs after exercise and preclinical studies demonstrating a potential tumor-suppressive effect of skeletal muscle-derived factors (such as myokines and miRNAs) suggest EVs as a potential delivery mechanism for skeletal muscle induced proteins and miRNAs in PCa (13,21,(42)(43)(44)(45)(46)(47)(48)58). Furthermore, the potential role of myokines in the facilitation of skeletal muscle-derived EV uptake in cancer has been recently proposed in a review article by Darkwah and co-workers (17).…”

“…However, the potential role of skeletal muscle-induced myokines, especially irisin, in skeletal muscle-derived EVs and cancer cell communication has been proposed in a recent review by Darkwah et al. ( 17 ) ( Figure 3 ).…”

“…Furthermore, previous studies have demonstrated high α V family integrins (such as α V β 6 and α V β 3 ) expression in PCa cell lines, and these transmembrane proteins can be transferred to other recipient cells ( 33 , 34 ), suggesting the potential role of irisin in increasing skeletal muscle-derived EVs and PCa cell communication. Although there is no research investigating the expression of FNDC5 in the membrane of skeletal muscle-derived EVs, the process of microvesicle biogenesis suggests the surface protein of the cell might be transferred to EVs ( 17 ). Taken together, it could be proposed that irisin-α V family integrins interaction can directly induce a tumor-suppressive effect on PCa cells and possibly increase skeletal muscle-derived EVs-PCa cell communication through an extracellular domain of FNDC5 (irisin)-integrin interaction.…”

“…Taken together, it could be proposed that irisin-α V family integrins interaction can directly induce a tumor-suppressive effect on PCa cells and possibly increase skeletal muscle-derived EVs-PCa cell communication through an extracellular domain of FNDC5 (irisin)-integrin interaction. This may increase the internalization of skeletal muscle-derived EVs into PCa cells to elicit the functional role of EV contents in PCa ( 17 ). Furthermore, circulating irisin may also interact with PCa cell-derived EV containing integrins and interfere with the delivery of PCa cell-derived EVs to the cells near PCa cells and contribute to remodeling the pre-metastatic environment ( 17 ).…”

“…One potential mechanism proposed is the involvement of extracellular vesicles (EVs) ( 15 , 16 ), as exercise-induced skeletal muscle-derived EVs may reduce cancer cell proliferation and metastasis ( 17 ). EVs are small membrane-surrounded structures released from various cells ( 18 ) that transfer bioactive molecules (including DNA, RNA, and proteins) from donor to acceptor cells ( 19 ).…”