COLBERT, L. H., V. MAI, S. N. PERKINS, D. BERRIGAN, J. A. LAVIGNE, H. H. WIMBROW, W. G. ALVORD, D. C. HAINES, P. SRINIVAS, and S. D. HURSTING. Exercise and Intestinal Polyp Development in APCMin Mice. Med. Sci. Sports Exerc., Vol. 35, No. 10, pp. 1662–1669, 2003.
Purpose: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise × sex interaction on polyp development and to begin to look at potential mechanisms.
Methods: Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m·min−1, 5% grade, 45 min·d−1, 5 d·wk−1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0–3), followed by treadmill running weeks 3–8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice.
Results: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 ± 0.7, mean ± SE) versus CON males (5.2 ± 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 ± 0.5 in EX; P = 0.01).
Conclusion: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.
Epidemiological evidence strongly suggests that there is a beneficial association between physical activity and colon cancer, with those who are more active having a lower risk of developing the disease than their sedentary peers (7). Despite the plethora of research on the protective role of physical activity in the etiology of colon cancer, there are few investigations into the potential mechanisms that might explain this association. A decreased stool transit time, lower prostaglandin and bile acid levels, a decrease in body fat, and lower levels of hormones such as insulin and insulin-like growth factor-1 (IGF-1) have all been suggested as potential mediators of the physical activity and colon cancer association (17); however, little evidence exists to support any of these mechanisms. Animal models that mimic aspects of human colon carcinogenesis would provide a tool in which to explore some of these possibilities and are necessary in order to establish the mechanisms that mediate the protective effect of exercise.
Few studies have examined the effect of exercise on intestinal tumor development in animals (1,6,21,27,28). Models of chemically induced carcinogenesis in rats have seen protective effects of both voluntary (1,21) and treadmill running exercise (27,28). Despite the positive results, a potential limitation of the treadmill exercise studies is the use of what might be considered an unreasonable duration of daily exercise (5 h·d−1), albeit at a slow speed (7 m·min−1) (27,28). Although the treadmill exercise studies did examine body weight (28) and body composition (27), no other potential mechanisms leading to reduced tumor development were examined in these early studies. Finally, although chemically induced models of carcinogenesis are useful, they may not be the ideal when trying to model human cancer, as the chemical treatment can induce severe and random genetic damage, and it is possible that exercise could affect the metabolism of the carcinogen.
Currently, numerous transgenic and induced-mutant mice are commercially available, some of which model human disease, including colorectal cancer. C57BL/6J Min+/− (Min) mice have a mutation in the Apc tumor suppressor gene that predisposes them to multiple intestinal adenomatous polyps within a few months of birth (18). Apc is the murine homolog of the human APC gene that is mutated in both familial adenomatous polyposis coli (FAP) and in sporadic tumors (24). Although the mice on the C57BL/6J background primarily develop noninvasive adenomas, they are believed to be a very useful model in which to explore questions related to intestinal neoplasia in humans (24). To date, we are the only group that we are aware of to have used this, or any other genetically engineered animal, to try and explore the relationships between exercise and cancers of various types.
A number of studies have shown protective effects of various chemopreventive agents on the development of polyps in Min mice, including nonsteroidal anti-inflammatory drugs (24) and dietary components such as fat and fiber (19,29). Previously, we trained Min mice on the treadmill and found no effect of exercise in the male and female mice as a group (6). Although there was some suggestion of a reduced polyp number with exercise among the males, the study lacked adequate statistical power to examine this difference by sex. Additionally, in that first study, we did not look at anything beyond body weight as potential mechanistic factors in this relationship. The purpose of the present study was to further explore the potential interaction between exercise and sex on polyp development and, additionally, to begin to look at potential mechanisms of the association.