BackgroundEpidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.MethodsIn Experiments 1 and 2, five-week old female ApcMin/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.ResultsIn the ApcMin/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In ApcMin/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors.ConclusionThese results indicate hat voluntary exercise inhibited intestinal tumorigenesis in ApcMin/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.

Earlier studies indicated that high dietary fat and obesity are associated with an increased risk of cancer at several organ sites in experimental animals and in humans. In a recent study we found that voluntary running wheel exercise decreased body fat and inhibited ultraviolet B light (UVB)-induced carcinogenesis in the epidermis of SKH-1 mice. In the present study we demonstrate that voluntary running wheel exercise stimulated UVB-induced apoptosis in the epidermis by a p53-independent mechanism, and voluntary exercise also stimulated apoptosis in UVB-induced tumors in tumor-bearing mice. Exercise had no effect in non-UVB-treated epidermis or in areas of the epidermis away from tumors in tumor-bearing mice. In addition, we found that removal of the parametrial fat pads (partial lipectomy) 2 weeks before UVB irradiation enhanced UVB-induced apoptosis. The results of our studies suggest that fat cells secrete substances that inhibit apoptosis in cells with DNA damage and possibly also in tumors. Our results help explain why exercise or various dietary regimens that decrease tissue fat inhibit carcinogenesis.carcinogenesis ͉ sunburn ͉ cancer prevention ͉ sun-induced skin cancer

In earlier studies we demonstrated that oral administration of caffeine or voluntary running wheel (RW) exercise decreased tissue fat (1-3), stimulated UVB light-induced apoptosis (3, 4), and inhibited UVB-induced carcinogenesis in SKH-1 mice (2, 5, 6). These treatments had no effect on body weight. It was of interest that the proapoptotic effects of these treatments were selective because they enhanced apoptosis in UVB-treated epidermis and in UVB-induced tumors, but the treatments had no effect on apoptosis in normal epidermis or in nontumor areas in tumor-bearing mice (1-5). The results of these studies suggest that the proapoptotic effects of caffeine administration and voluntary exercise are important for the inhibitory effects of these regimens on UVB-induced carcinogenesis.In the present work, we determined the effects of a combination of voluntary RW exercise and oral administration of caffeine on UVB-induced apoptosis in SKH-1 mice. The results indicated a greater than additive stimulatory effect of voluntary RW exercise, when combined with a low dose of caffeine, on UVB-induced apoptosis. Results Effects of Voluntary RW Exercise and Oral Administration of Caffeine on Body Weight, Food Consumption, and Fluid Consumption in SKH-1Mice. Treatment of female SKH-1 mice with RW, caffeine (0.1 mg/ml in the drinking water), caffeine (0.4 mg/ml), RW ϩ caffeine (0.1 mg/ml) or RW ϩ caffeine (0.4 mg/ml) for 2 weeks did not have a statistically significant effect on body weight or food consumption. In an earlier study, we found that voluntary RW exercise for several months increased both food consumption and fluid intake without having an effect on body weight (2).In the present study, the average daily fluid consumption Ϯ SE. by control mice or mice treated with RW, caffeine (0.1 mg/ml), caffeine (0.4 mg/ml), RW ϩ caffeine (0.1 mg/ml), or RW ϩ caffeine (0.4 mg/ml) for 2 weeks was 7.97 Ϯ 0.22 ml, 9.66 Ϯ 0.14 ml (21.3% 1; P ϭ 0.006), 9.76 Ϯ 0.19 ml (22.5% 1; P ϭ 0.004), 8.53 Ϯ 0.42 ml (7.0% 1; P Ͼ 0.1), 11.45 Ϯ 0.39 ml (43.7% 1; P Ͻ 0.001), or 9.36 Ϯ 0.67 ml (17.4% 1; P ϭ 0.02), respectively (results from two experiments). The daily dose of caffeine in mice treated with caffeine (0.1 mg/ml), caffeine (0.4 mg/ml), RW ϩ caffeine (0.1 mg/ml), or RW ϩ caffeine (0.4 mg/ml) was 38, 130, 43, or 144 mg/kg, respectively (average of two experiments). There was some variation in RW activity among different mice in the RW group, but the relatively small SE among different mice for tissue fat reduction in the RW group suggests relatively small interindividual differences in RW activity among the different mice.Although it was difficult to determine the distance run by individual RW mice because there were five mice per cage and sometimes more than one mouse at a time was on the RW, we estimate that the RW mice ran Ϸ2 miles per day, and this distance was not significantly different from that run by the RW ϩ caffeine (0.1 mg/ml) or from the RW ϩ caffeine (0.4 mg/ml) group (average of two experiments). Effect of Voluntary RW Exercis...

Treatment of p53(-/-) mice orally with caffeine, voluntary exercise or their combination for 2 weeks prior to a single irradiation with UVB (i) decreased the weight of the epididymal fat pads by 22, 40 and 56%, (ii) decreased the thickness of the dermal fat layer by 10, 26 and 42%, (iii) increased the number of apoptotic sunburn cells by 29, 100 and 489%, (iv) increased the number of caspase-3-positive cells by 33, 117 and 667% and (v) increased the number of mitotic cells with cyclin B1-positive staining by 40, 210 and 510%, respectively. Pearson's correlation coefficient indicated a statistically significant inverse relationship between the level of tissue fat and the number of mitotic cells with cyclin B1 in p53(-/-) mice but not in p53(+/+) littermates. Western blot analysis indicated that treatment of p53(-/-) mice with caffeine together with exercise increased the level of cyclin B1 significantly more than in p53(+/+) mice. p53(-/-) mice, but not p53(+/+) mice, treated with caffeine during exercise exhibited a dramatic decrease in the level of survivin. Our results suggest that voluntary exercise in combination with oral caffeine may exert a synergistic increase in UVB-induced apoptosis and that tissue fat may be a more important modulator of apoptosis and carcinogenesis in p53-deficient mice than in p53-normal mice. The stimulatory effects on apoptosis in p53(-/-) mice by the combination treatment might be associated with increased levels of cyclin B1 and decreased levels of survivin.

UVB-pretreated SKH-1 mice were treated with water, caffeine (0.1 mg/ml), voluntary running wheel exercise (RW) or caffeine together with RW for 14 weeks. Treatment of the mice with caffeine, RW, or caffeine plus RW decreased skin tumors per mouse by 27, 35 and 62%, and the tumor volume per mouse was decreased by 61, 70 and 85%, respectively. In mechanistic studies, mice were treated with water, caffeine, RW, or caffeine plus RW for 2 weeks prior to a single irradiation with UVB. Caffeine plus RW increased RW activity by 22% when compared with RW alone. Caffeine ingestion was not significantly different between groups. Treatment of mice with caffeine plus RW for 2 weeks decreased the weight of the parametrial fat pads and stimulated the formation of UVB-induced apoptosis to a greater extent than treatment with caffeine or RW alone. An antibody array revealed that caffeine plus RW administered to mice fed a high fat diet and irradiated with UVB decreased the epidermal levels of LIX, sTNFR1 and MIP-1γ. Overall, caffeine during RW exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis.