The search for a prostate cancer (PCa) cure involves general practitioners, internal medicine doctors, surgeons, radiologists, oncologists, and biologists—to name just a few. It may surprise you to learn that your personal trainer or coach may also have something to offer in terms of defeating PCa and other tumor cancers: exercise! As surprising as it may sound, physical exercise actually unleashes anti-tumor effects. It does so in the form of tiny particles released into circulation by working muscle cells. These particles are called an extracellular vesicle (EV).

Extracellular vesicles (EVs)

Almost every cell in the body sends and receives communication other cells. EVs are like efficient Western Union telegrams containing concise messages. The interior of each cell creates instructions in the form of molecules like messenger RNA (mRNA). It packs this cargo into a nano-sized spherical membrane, or sac, which has identification markers on the outer surface of the membrane. It then ejects this message-containing particle out into the cell’s external environment (“extracellular” means outside the cell, and “vesicle” means a small fluid-filled sac). From there, as the EV circulates, it will be intercepted by another cell near or far away. That cell has surface receptors that recognize the messenger’s ID tags, and clears it for uptake into itself.

Once inside the acceptor cell, the vesicle releases its cargo into that cell’s internal processes. When it decodes the instructions and implements them, it can alter the acceptor cell’s behavior or function by influencing gene regulation. This means switching genes on or off, which will change what the cell is programmed to do. According to Rybak & Robatzek, “Cell-to-cell communication is ubiquitous [that is, everywhere] in all biological systems. As a means to manage species interactions, secretion, and delivery of molecular signals in the extracellular environment is essential for species survival.”^[i]

EVs come in two flavors: good guys and bad guys. Healthy cells are not the only EV factories. Cancer cells produce EV bad guys that work against survival. A research study by Zhang, et al. (2021) notes, the EV cargos from cancer cells “… are considered to be biologically influential in cancer progression, metastasis, and development of drug resistance.”^[ii] The team of authors from China and Australia cite previous research with PCa patients showing that 11 specific microRNAs (miRNA) that interact with mRNA were “substantially increased” in circulating EVs from patients compared to healthy individuals. Two of these miRNAs were “significantly increased in patients with metastatic prostate cancer … compared to patients with localized prostate cancer.” Furthermore, in men with castration-resistant PCa (does not respond to androgen deprivation therapy), those with a high level of two combined miRNAs had shorter overall survival than those with a lower level of that same combination.
PCa EVs can promote changes in both healthy and PCa cells that foster tumor growth, progression into more aggressive disease, and cancer metastasis.

PCa, exercise, and the EV good guys

As dire as this may sound, the Zhang paper brings news of EV hope. Here’s where exercise comes in. I have already posted many blogs describing proven benefits of exercise for PCa patients. For instance, exercise extends life for metastatic PCa patients, lowers PSA and slows tumor activity among those on Active Surveillance, protects against inflammation which can be a PCa precursor, supports treatment success, and even helps manage anxiety over having PCa. But how, exactly, does it work?

The Zhang paper offers a detailed explanation for the biologic role of EVs from healthy muscle cells when they are exercised. There is existing evidence that exercise raises the level of EVs in circulation and influences the nature of their contents in terms of healthy regulatory mRNAs, miRNas, and other proteins. Exercise studies with healthy individuals in which muscle EVs are measured and analyzed include cycling, treadmill, swimming, and cardio stress tests at various exertion and duration points. Such studies show that levels of circulating EVs are highest at peak intensity, and remain for some time before diminishing during rest periods. The authors write that a “…significant difference in EVs concentration was shown in all exercise groups compared to the non-exercise group.”

With regard to PCa, “Among the physiological alterations induced by exercise, the tumor-suppressive role of skeletal muscle secreted proteins (myokines) and miRNAs in PCa suggests a regulatory role of skeletal muscle-derived EV-containing proteins in PCa.” Just as EVs from PCa cells can be received by healthy cells who unwittingly take in instructions to alter themselves toward cancer, apparently the reverse is also true. Clinical exercise trials that show “…elevation of skeletal muscle-induced EVs after exercise” also demonstrated “…a potential tumor-suppressive effect of skeletal muscle-derived factors (such as myokines and miRNAs).” This suggests that exercise-induced muscle EVs offer a potential delivery system to alter PCa cells so they are nonthreats, or even self-destructive.

In closing, the authors point out that research into skeletal EVs vs. PCa is still early. Also, the research into exercise-induced muscle-derived EVs has been with healthy subjects, not cancer patients, so more needs to done with patients. They remind us that PCa patients on androgen deprivation to manage advanced disease have medication side effects that include loss of muscle mass and gain of fat mass, so their “physiology of skeletal muscle biogenesis may differ from that of healthy subjects.” Finally, “the direct communication between skeletal muscle cells and PCa cells via EVs is yet to be reported.” Nonetheless, I believe this study is very promising because of its deeper biological exploration of why and how exercise has been proven to benefit PCa patients. Let’s give a big hand for EVs!

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Rybak K, Robatzek S. Functions of Extracellular Vesicles in Immunity and Virulence. Plant Physiol. 2019 Apr;179(4):1236-1247.
[ii] Zhang Y, Kim JS, Wang TZ, Newton RU et al. Potential Role of Exercise Induced Extracellular Vesicles in Prostate Cancer Suppression. Front Oncol. 2021 Sep 14;11:746040.