Running suppresses tumor growth in mouse tumor models by increasing natural killer cell infiltration.
Major finding: Running suppresses tumor growth in mouse tumor models by increasing natural killer cell infiltration.
Mechanism: Running induces plasma IL6 and epinephrine, which mobilize IL6-sensitive natural killer cells.
Impact: Exercise may enhance natural killer cell–mediated antitumor immune responses.
Epidemiologic studies have suggested that regular exercise protects against cancer development and recurrence, but the mechanisms by which regular exercise may protect against cancer remain unknown. Pedersen and colleagues investigated the effects of wheel running on tumor incidence and progression in multiple mouse tumor models. In one example, four weeks of wheel running prior to subcutaneous melanoma cell implantation markedly reduced tumor growth compared to non-running control mice and inhibited lung metastasis when cells were intravenously injected. Running also significantly reduced tumor incidence in chemically induced liver tumors, decreased tumor volume in a lung carcinoma model, and delayed the onset of spontaneous melanoma in transgenic mice. Microarray analysis of subcutaneous melanomas revealed that running upregulated a number of immunologic and inflammatory pathway genes. Moreover, tumors from running mice exhibited elevated infiltration by natural killer (NK) cells, and depletion of NK cells abrogated the antitumor effects of running. Mechanistically, running was associated with increased serum levels of epinephrine (EPI), which was required for the running-induced reduction in tumor volume. Plasma levels of IL6 also increased during exercise, and EPI reduced the fraction of IL6Rα-positive splenic NK cells, suggesting that IL6-sensitive NK cells were mobilized to tumor sites. Consistent with these findings, anti-IL6 antibodies prevented the exercise-induced reduction in tumor growth and reduced tumor infiltration by NK cells. Taken together, these data indicate that exercise can reduce tumor initiation and progression via an EPI-dependent mobilization of IL6-sensitive NK cells, and suggest a potential mechanism whereby exercise may enhance NK cell antitumor activity in multiple cancer types.