Exercise-Induced Extracellular Vesicles Delay the Progression of Prostate Cancer

Abstract

Increasing evidence suggests that regular physical exercise not only reduces the risk of cancer but also improves functional capacity, treatment efficacy and disease outcome in cancer patients. At least partially, these effects are mediated by the secretome of the tissues responding to exercise. The secreted molecules can be released in a carrier-free form or enclosed into extracellular vesicles (EVs). Several recent studies have shown that EVs are actively released into circulation during physical exercise. Here, we for the first time investigated the effects of exercise-induced EVs on the progression of cancer in an F344 rat model of metastatic prostate cancer. Although we did not observe a consistent increase in the circulating EV levels, RNA sequencing analysis demonstrated substantial changes in the RNA content of EVs collected before and immediately after forced wheel running exercise as well as differences between EVs from runners at resting state and sedentary rats. The major RNA biotype in EVs was mRNA, followed by miRNA and rRNA. Molecular functions of differentially expressed RNAs reflected various physiological processes including protein folding, metabolism and regulation of immune responses triggered by the exercise in the parental cells. Intravenous administration of exercise-induced EVs into F344 rats with orthotopically injected syngeneic prostate cancer cells PLS10, demonstrated reduction of the primary tumor volume by 35% and possibly—attenuation of lung metastases. Hence, our data provide the first evidence that exercise-induced EVs may modulate tumor physiology and delay the progression of cancer.

The Influence of Exercise-Associated Small Extracellular Vesicles on Trophoblasts In Vitro

“…Relatively few studies to date have determined the physiological impact of exercise-associated sEVs on the biological functions of target cells, and none have been conducted on trophoblasts or cells constituting the maternal–fetal interface. The majority of work on the physiological consequences of exercise-associated sEVs involve animal models, where their interactions have been shown to delay prostate cancer progression [ 45 ], provide sustained cardioprotection [ 40 ], and elicit beneficial effects in ischemic stroke [ 46 ]. In humans, sEVs obtained after blood flow-restricted resistance exercise in healthy men were found to increase the proliferation of fibro-adipogenic progenitor cells [ 41 ].…”

Exploiting the therapeutic potential of contracting skeletal muscle-released extracellular vesicles in cancer: Current insights and future directions

“…Regarding the potential anticancer effect of EVs derived from the plasma of exercised subjects, only one preclinical study is known to have demonstrated the tumor-suppressive effect of such EVs. In this study by Sadovska et al [ 12 ], regular injection of exercise-induced EVs in tumor-bearing rats resulted in a reduction of primary tumor growth by approximately 35% and a possible delay in the development of lung metastases. When analyzing the cargo of exercise-induced EVs, these authors found upregulation of genes encoding proteins involved in metabolic processes, such as Notum (palmitoleoyl-protein carboxylesterase), Pctp (phosphatidylcholine transfer protein), and Cyp4b1 (cytochrome P450, family 4, subfamily b, polypeptide 1).…”

“…However, research on SkM-derived EVs is currently limited, as only a handful of studies have examined their molecular cargo and the impact of different exercise regimens on their release [ 9 – 11 ]. Furthermore, there is a lack of research investigating the specific role of SkM-derived EVs in cancer development and progression [ 12 , 13 ].…”

Potential involvement of circulating extracellular vesicles and particles on exercise effects in malignancies

“…They showed that administration (i.v.) of EVPs obtained from rats submitted to regular exercise (5 weeks) reduced the tumor size (primary tumor volume by 35%) and lung metastasis using a syngeneic orthotopic prostate cancer model (13).…”

“…Several subclasses of EVPs, such as exosomes, microvesicles, and apoptotic bodies have been described (9)(10)(11) and have the ability to transfer bioactive molecules, such as proteins, lipids, messenger RNAs (mRNAs), and miRNA (12). Recently, Sadovska et al, (13), suggested EVPs as the central mechanism of exercise induced changes in prostate cancer, specifically on the progression of cancer in a metastatic prostate cancer model. They showed that administration (i.v.)…”