Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data: Beyond the Abstract
There is increasing interest in whether the benefits of exercise for cancer patients extends beyond helping prevent and/or mitigate the adverse side effects of cancer treatment to directly inhibiting tumor initiation and progression.1
For example, observational epidemiological studies show regular exercise, at a level similar to that recommended to reduce cardiovascular disease, results in a 25% decrease in breast cancer risk, and a 30-40% decrease in colon cancer risk 2,3. Numerous studies have shown that physical activity decreases prostate cancer incidence by 16-35%, and could reduce the risk of death from prostate cancer by as much as 61% (reviewed in 4). However, these epidemiological observations should be strengthened by pre-clinical animal work to confirm biological plausibility. Additional benefits of pre-clinical studies are that researchers can reduce confounding factors, such as diet and co-morbidities, and they can more carefully dictate exercise prescription. Exercise prescriptions can vary by type, intensity, duration and frequency- each of these variables must be considered before clinicians can prescribe exercise to cancer patients.
We conducted a systemic critical analysis of the effects of aerobic exercise on cancer in pre-clinical rodent models 5. We considered tumor initiation, growth and metastasis. Our review ultimately considered the findings of 53 papers that prescribed repeated bouts of aerobic exercise to rodents. These included two papers with prostate tumor cell transplants 6,7 and one paper that used transgenic mice with a genetic alteration to promote prostate tumor growth 8.
In general, exercise was associated with an anti-cancer effect. Of the 24 papers that examined tumor incidence/development, 58% reported that exercise decreased tumor initiation or multiplicity. Thirty-three papers examined tumor growth/progression with 64% reporting that exercise slowed tumor growth. Jones et al. reported that primary prostate tumor growth was similar in sedentary and exercising mice (though metastatic incidence was reduced) 7, but Gueritat et al. showed slower prostate tumor growth in exercising rats compared to sedentary controls 6. The final prostate cancer study, conducted by Esser et al., was unique because they stratified their animals based on the average distance run each day 8. This study reported that mice that ran more than 5 km/day had a 57% reduction in high grade neoplasias compared to mice that ran less than 5 km/day.
It is important to note that in just the three prostate cancer studies highlighted above, we found heterogeneity in many aspects of study design: Two studies used a murine voluntary wheel running model 7,8, while the third used a forced treadmill model in rats 6. As stated above, two papers transplanted prostate tumor cells, though one of these was an orthotopic transplant 7, and one was sub-cutaneous 6. The third paper used a transgenic mouse model 8.
The considerable heterogeneity extended to all 53 studies we reviewed. Overall, we reported studies using 15 different types of tumors induced by six different methods and 5 different types of exercise. Exercise models were further complicated by difference in frequency, the time exercise was initiated relative to tumor appearance or transplant, and different intensity permutations (such as treadmill incline or additional weight burden in swimming models. Finally, research groups differed in the types of tumor-related data collected (such as tumor growth, incidence, or metastasis) and the level and type of mechanistic correlative studies, if underlying mechanisms were investigated at all. The heterogeneity across the 53 studies precluded any sophisticated statistical analysis, and at this time we are unable to draw any meaningful conclusions specific to tumor or exercise type.
To this end, we put forth a number of suggestions for future preclinical exercise oncology research. Although we recognize that different research groups will have individual preferences for the type of tumor and exercise model they employ, we urge researchers to at least standardize the methods reported, and include as much information as possible regarding exercise prescription and similar of environmental exposures and handling of animals in the control groups. With the increased focus on immunotherapies, exercise oncology studies could be strengthened by using syngeneic tumor models in immunocompetent mice, rather than human tumor xenografts in immunocompromised animals.
Finally, as the field progresses, we strongly encourage exercise oncology researchers to increase the level of sophisticated mechanistic analyses. With new oncology technologies available, researchers can delve deeper into the molecular and genomic correlates of exercise treatment effects. Such analyses will promote acceptance of “exercise as a drug” within the clinic, which will be necessary for its full therapeutic potential to be realized.
Written by: Kathleen A Ashcraft, Mark W. Dewhirst and Lee W. Jones
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References:
1. Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain, behavior, and immunity 2013;30 Suppl:S75-87.
2. Friedenreich CM, Woolcott CG, McTiernan A, et al. Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:1458-66.
3. Gammon MD, Schoenberg JB, Britton JA, et al. Recreational physical activity and breast cancer risk among women under age 45 years. American journal of epidemiology 1998;147:273-80.
4. Wekesa A, Harrison M, Watson RW. Physical activity and its mechanistic effects on prostate cancer. Prostate cancer and prostatic diseases 2015;18:197-207.
5. Ashcraft KA, Peace RM, Betof AS, Dewhirst MW, Jones LW. Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data. Cancer research 2016.
6. Gueritat J, Lefeuvre-Orfila L, Vincent S, et al. Exercise training combined with antioxidant supplementation prevents the antiproliferative activity of their single treatment in prostate cancer through inhibition of redox adaptation. Free radical biology & medicine 2014;77:95-105.
7. Jones LW, Antonelli J, Masko EM, et al. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer. Journal of applied physiology 2012;113:263-72.
8. Esser KA, Harpole CE, Prins GS, Diamond AM. Physical activity reduces prostate carcinogenesis in a transgenic model. The Prostate 2009;69:1372-7.