Abstract 364: Exercise slows tumor progression and normalizes tumor vasculature in murine models of breast cancer.

Abstract

Abstract The effect of endurance exercise to improve post-ischemia perfusion of normal tissues is established but whether such effects extend to hypoxic solid tumors is largely uninvestigated. Thus, we evaluated the hypothesis that exercise slows tumor growth and improves the structure and function of tumor blood vessels, resulting in decreased hypoxia and increased effectiveness of cyclophosphamide chemotherapy. To investigate the effects of exercise on tumor microenvironment, we utilized voluntary wheel running after tumor cell implantation in two orthotopic models of murine breast cancer: ER(-) 4T1 breast tumor cells in BALB/c mice and ER(+) E0771 breast tumor cells in C57Bl/6 mice. Endurance exercise significantly increased microvessel density (CD31, p<0.003), vessel maturity (co-localization of NG2 and desmin with CD31, p<0.003), and perfusion (ADCperf, p<0.05), which resulted in significant reductions in intratumoral hypoxia (EF5, p<0.002). This was associated with significant inhibition of tumor growth (p<0.004), and increased apoptosis compared with sedentary controls (cleaved caspase-3, p<0.05). Next, given that hypoxia is a major cause of chemoresistance, we tested whether exercise-induced improvements in perfusion and reduction of hypoxia could improve the efficacy of conventional chemotherapy. The combination of exercise plus cyclophosphamide was associated with significantly prolonged growth delay compared with exercise or chemotherapy alone (p<0.01). In this work, we provide the first conclusive evidence that exercise may do more than decrease symptoms and improve quality of life for cancer patients. Our data suggest that exercise may be an effective adjunct therapy to reduce tumor hypoxia leading to enhanced efficacy of anticancer therapy. Funding: ASB is supported by DOD BC093532. LWJ is supported by NIH CA143254, CA142566, CA138634, CA133895 and funds from George and Susan Beischer. MWD is supported by NIH CA40355. Citation Format: Allison S. Betof, Lee W. Jones, Mark W. Dewhirst. Exercise slows tumor progression and normalizes tumor vasculature in murine models of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 364. doi:10.1158/1538-7445.AM2013-364