Research Blog

Exercise Helps the Immune System Fight Cancer

Tumor attacked by white blood cell

A study finds that the adrenaline or epinephrine released with exercise enhances NK cell mobilization to tumorous growths. NK cells are a critical component of the innate immune system that function to kill cancerous cells and virally infected cells.

We have previously explored how exercise can weaken the immune system. Open window theory states that the immune system is weakened 3-72 hours after a bout of intense endurance exercise due to a skeletal muscle inflammation mediated disruption in cytokine levels. Cytokines are small signaling molecules that guide inflammatory cells to areas of infection or damage. Immune system dysfunction probably explains the increased susceptibility to infectious disease seen in athletes after an intense bout of exercise. Although intense exercise may increase one’s susceptibility to infection, research suggests that exercise boosts the body’s ability to fight cancer.

Epidemiological studies have previously noted that exercise protects individuals  from cancer, in addition to well-known chronic diseases like obesity, diabetes and coronary heart disease. Recent evidence suggests that the immune system plays a vital role in exercise’s ability to help fight off cancer.

A novel study published in the March 2016 issue of Cell Metabolism has been garnering interest because it demonstrated that epinephrine, IL-6, and Natural Killer cells all play an integral part in reducing tumors in exercised mice. Epinephrine, more commonly referred to as adrenaline, is an important signal molecule that allows the sympathetic nervous system to alert the body of a “fight or flight” response. Epinephrine ramps up the heart rate, reduces gut activity by constricting intestinal blood flow and increases blood flow to skeletal muscle. These actions make epinephrine an important signaling molecule during exercise (and explains why patient’s on beta-blockers, an anti-hypertension medication, have reduced maximal exercise capacity). IL-6 is a cytokine, or immune signaling molecule, that induces fever and stimulates the production of additional immune system proteins called acute phase reactants. Natural killer cells are a special innate immune system cell that destroys the body’s own cells when they are damaged by viral infection or have become cancerous by using special cytotoxic ("cell-killing”) proteins called perforin and granzyme.

The aforementioned study found that mice with running wheels for voluntary exercise had reduced tumor incidence and growth (Voluntary Running Suppresses Tumor Growth through Epinephrine and IL-6 Dependent NK Cell Mobilization and Redistribution, 2012. Pedersen, et al.). Interestingly, this effect was found to hold up for different tumor models (i.e. melanoma, etc.) and anatomical locations. 

Mice were injected with a carcinogenic toxin called diethylnitosamine, which induces tumors within 10 months in mice. Mice were housed with running wheels or without running wheels. Although 31% of running mice developed tumors, 75% of the control mice developed tumors. In addition, the tumors in running mice were smaller by volume and weight. This finding is shown in the figure below.

Bar graph showing tumor volume is reduced in exercised mice. Average tumor volume (mm3) in mice housed with running wheels (EX, n=12) and without running wheels (CON, n=11). Subcutaneous B16F10 tumors in C57BL/6 mice. *p<0.05, Students T-test

What was mediating the difference in tumor burden between running and control mice? The running mice had increased Natural Killer (NK) cells in their tumors. Recall that NK cells destroy cancerous cells. In fact, control mice had barely detectable levels of NK cells in their tumors. The NK cells in both mice groups had similar cell killing ability. The researchers discovered epinephrine (adrenaline) to be implicated in the NK cell recruitment. Blocking epinephrine with the anti-hypertensive medication propanol during exercise led to a blunted exercise anti-tumor effect. Perhaps most interesting was that an injection of epinephrine in control, non-running mice led to a reduction in tumor burden that was nearly as large as the reduced burden seen in running mice. 

IL-6 is an interleukin, or immune system signaling molecule, that was also implicated in mediating the exercise-induced inhibition of tumor growth. Blocking IL-6 using an antibody negated the exercised-induced reduction in tumor burden. However, unlike epinephrine, an IL-6 injection independent of running had no effect on tumor burden in non-running control mice. In addition, other pro-inflammatory cytokines such as IL-1 and iNOS were found to be up-regulated in the tumors of running mice relative to control mice.

Proposed mechanism that voluntary running in mice suppresses tumor growth. Exercise mobilizes NK cells via epinephrine and IL-6 to redistribute to tumors. NK cells are immune cells that then destroy the cancerous cells that compose the tumor. Epinephrine, also known as adrenaline, is produced during exercise. IL-6 is an immune system signaling molecule.

Therefore, running or exercise in general may reduce cancer incidence by increasing NK cell mobilization to cancerous cells. It appears this phenomenon is mediated by epinephrine and immune cytokines such as IL-6. That an epinephrine injection is able to reduce tumor incidence in mice, raises the exciting prospect that an epinephrine injection could be utilized to help fight cancer in patients who are unable or unwilling to exercise. Epinephrine injections are currently used to raise blood pressure in individuals whose are dangerously hypotensive, such as via an anaphylactic reaction to a bee sting. However, it also raises the question to what extent do beta-blockers increase tumor incidence by eliminating the anti-cancer benefits of epinephrine. Of course, the benefits and adverse events seen in mice models may not extrapolate to humans. More research will be necessary to fully understand the anti-cancer immunological benefits of exercise in humans, and whether there are practical lifestyle or pharmaceutical therapeutics to be gained from this research.

In conclusion, running mice were found to have significantly reduced incidence of tumors relative to non-running controls apparently via a NK cell and epinephrine immunological mechanism. This raises the tantalizing prospect of adding epinephrine and exercise to our arsenal of weapons to battle cancer.

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