Abstract SY22-02: Exercise and cancer progression: Preclinical evidence
Authors: Dewhirst Mark W. , Ashcraft Kathleen , Jones Lee 
Published: July 2016

Abstract
A major objective of the emerging field of exercise-oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of certain forms of cancer, while emerging data suggest that post-diagnosis exercise exposure may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies that validate the biological efficacy of exercise, identify the optimal “dose” and pinpoint mechanisms of action. However, as we reviewed the extant literature, we were struck by substantial heterogeneity in the methods and means of analysis across pre-clinical exercise studies. As a result, we were unable to derive any cardinal features of exercise studies that could and should be adhered to. Furthermore, exercise protocols employed in many pre-clinical trials would never translate directly to human studies. At a minimum, we would argue that such studies must be conducted to mirror human studies as closely as possible.
We found that mice that voluntarily run on wheels ad libitum exhibit slowed tumor growth compared with sedentary controls. Further, we observed improved perfusion in multiple tumor models. Interestingly, the increases in perfusion are associated with increases in HIF-1 and VEGF. Although upregulation of VEGF is normally associated with reduced vascular maturity, exercise increased vascular maturity, as assessed by association of CD31 (an endothelial cell marker) and desmin, a marker of pericytes was observed with animals that exercised. The improvement in perfusion was associated with concomitant reduction in hypoxia in the primary tumor. This has important clinical implications, as we observed enhanced anti-tumor effects when voluntary exercise was combined with either cyclophosphamide or radiotherapy in the 4T1mouse mammary carcinoma model. We further found that exercise reduced metastatic burden alone and when combined with radiotherapy to the primary tumor site. These are the first pre-clinical studies that have examined the value of exercise combined with chemo / radiotherapy. The results lead us to suggest that exercise intervention in human patients undergoing chemotherapy and/or radiotherapy can enhance local tumor control as well as reducing risk for metastasis. Future pre-clinical studies will identify mechanisms underlying these effects as well as establishing optimal exercise regimens to achieve enhanced treatment response.
Work supported by a grant from the NIH/NCI CA40355
Citation Format: Mark W. Dewhirst, Kathleen Ashcraft, Lee Jones. Exercise and cancer progression: Preclinical evidence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY22-02.