Exercise Attenuates Tumor Growth Via Beta-2-Adrenergic Receptor Signaling In Murine Lymphoma

Abstract

PURPOSE: Voluntary exercise has been shown to reduce tumor burden in several murine cancer models. The frequent mobilization and redistribution of effector lymphocytes (e.g. NK-cells, CD8+ T-cells) with exercise has been shown to enhance the presence of tumor infiltrating lymphocytes, potentially contributing to reductions in tumor growth. We have shown in humans that non-selective β1 + 2 adrenergic receptor (AR) blockade abrogates effector lymphocyte mobilization, whereas selective β1-AR blockade augments the response. We therefore hypothesize that β1 + 2-AR blockade will inhibit, whereas selective β1-AR blockade will enhance, the anti-tumor effects of exercise in an exercise-sensitive mouse model of lymphoma. METHODS: 8-12 week old male Balb/C mice were injected subcutaneously in the flank with 1 x 106 A20 lymphoma cells and assigned to either sedentary or exercise conditions. Groups were then further divided to include one of three different types of chow: (1) standard NIH chow, (2) NIH chow milled with a non-selective β1 + 2-AR antagonist (nadolol), and (3) NIH chow milled with a selective β1-AR antagonist (bisoprolol). Tumor progression was assessed with calipers every 3-4 days for 6 weeks. RESULTS: At week 6, sedentary mice consuming normal chow (3974.63 ± 557.80 mm3), nadolol chow (2943.94 ± 716.75 mm3), or bisoprolol chow (3088.62 ± 611.21 mm3) had comparable tumor burden. Exercising mice consuming normal chow or bisoprolol chow had significantly reduced tumor burden at week 6 relative to sedentary mice (882.56 ± 461.10 and 1398.50 ± 550.32 mm3, respectively; p < 0.0001). Interestingly, exercising mice consuming nadolol chow had tumor burden significantly greater than other exercising mice and were comparable to sedentary groups (3136.25 ± 883.93 mm3; p < 0.01). CONCLUSIONS: These data indicate that the protective effects of voluntary wheel running on murine lymphoma growth are β2-AR but not β1-AR dependent. Whether these effects are due to catecholamine signaling in the tumor or to a greater level of tumor infiltration by mobilized effector lymphocytes remains to be determined. These findings may have implications for patients taking β-blockers during cancer treatment and provide insight into the mechanisms underpinning immune cell mobilization and tumor infiltration with exercise.