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Carcinogenesis Advance Access originally published online on May 13, 2006
Carcinogenesis 2006 27(10):2108-2115; doi:10.1093/carcin/bgl057
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice

Laura Michna1,{dagger}, George C. Wagner3,{dagger}, You-Rong Lou2, Jian-Guo Xie2, Qing-Yun Peng2, Yong Lin4,5, Kirsten Carlson3, Weichung Joe Shih4,5, Allan H. Conney2,5 and Yao-Ping Lu2,*

1 Joint Graduate Program in Toxicology, Department of Chemical Biology, Ernest Mario School of Pharmacy Piscataway, NJ 08854, USA
2 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey Piscataway, NJ 08854, USA
3 Department of Psychology, Rutgers, The State University of New Jersey Piscataway, NJ 08854, USA
4 The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway NJ 08854, USA
5 The Cancer Institute of New Jersey, New Brunswick NJ 08901, USA

*To whom correspondence and requests for reprints should be addressed at: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA. Tel: +1 732 445 3400; Fax: +1 732 445 0687; Email: sago{at}rci.rutgers.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Earlier studies showed that oral administration of green tea or caffeine to SKH-1 mice inhibited ultraviolet B light (UVB)-induced skin carcinogenesis, decreased dermal fat thickness and increased locomotor activity. In the present study, the effects of voluntary running wheel exercise on thickness of dermal fat as well as on UVB-induced tumorigenesis in SKH-1 mice were studied in UVB-initiated high-risk and UVB-induced complete carcinogenesis models. In the high-risk model, animals were exposed to UVB (30 mJ/cm2) 3 times/week for 16 weeks. For 14 weeks subsequent to UVB exposure, half of the animals had access to running wheels in their cages whereas the other half did not. In the complete carcinogenesis model, animals were exposed to UVB (30 mJ/cm2) 2 times/week for 33 weeks. From the beginning, half of the animals had access to running wheels whereas the other half did not. At the conclusion of each study, body weights were not different between groups, although animals with running wheels consumed significantly more food and water than animals without running wheels. In addition, animals with running wheels had decreases in parametrial fat pad weight and thickness of the dermal fat layer. In both UVB-initiated high-risk and complete carcinogenesis models, voluntary running wheel exercise delayed the appearance of tumors, decreased the number of tumors per mouse and decreased tumor volume per mouse. Histopathology studies revealed that running wheel exercise decreased the number of non-malignant tumors (primarily keratoacanthomas) by 34% and total tumors per mouse by 32% in both models, and running wheel exercise decreased the formation of squamous cell carcinomas in the UVB-induced complete carcinogenesis model by 27%. In addition, the size of keratoacanthomas and squamous cell carcinomas were decreased substantially in both models. The effects described here indicate that voluntary running wheel exercise inhibits UVB-induced skin tumorigenesis and may also inhibit tumor growth.

Abbreviations: GEE, generalize estimating equation; UVB, ultraviolet B light


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Previous studies in our laboratory found that oral administration of green tea or caffeine to SKH-1 mice inhibited ultraviolet B light (UVB)-induced skin carcinogenesis (1–3). Although there was no effect on body weight, administration of green tea and caffeine reduced the weight of the parametrial fat pads, decreased the thickness of the dermal fat layer and increased the thickness of the dermal muscle layer (3,4). Since caffeine is a central nervous system stimulant and because administration of caffeine inhibited UVB-induced skin carcinogenesis, the effect of oral green tea and caffeine on locomotor activity was investigated in our laboratory. The same concentrations of green tea and caffeine that were used in our UVB carcinogenesis studies were found to significantly increase locomotor activity. Administration of 0.6% green tea (6 mg tea solids/ml) increased total 24 h locomotor activity by 47%, compared with water, and 0.04% caffeine (0.4 mg/ml; the same concentration of caffeine found in the 0.6% green tea solution) increased total 24 h locomotor activity by 24%, compared with water (4). A small (9%) increase in locomotor activity was caused by 0.6% decaffeinated green tea, but decaffeinated green tea was found to have little or no inhibitory effect on UVB-induced skin carcinogenesis (1,2). The significant increase in locomotor activity by green tea and caffeine led us to investigate whether increased voluntary locomotor activity in the form of running wheel exercise would inhibit UVB-induced skin tumorigenesis. In the present study, we describe the effect of voluntary running wheel exercise to inhibit skin tumorigenesis in tumor-free mice previously treated with chronic UVB (high-risk mice). The ‘high risk mouse’ is a useful animal model that may be comparable with humans previously exposed to moderate/high levels of sunlight who have a high risk of developing skin cancers later in life even in the absence of continued heavy sunlight exposure. The effect of voluntary running wheel exercise to inhibit skin tumorigenesis in mice continuously exposed to UVB (a complete carcinogenesis model) was also investigated.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals and chemicals
Female SKH-1 hairless mice (6–7 weeks old) were purchased from the Charles River Breeding Laboratories (Kingston, NY), and the animals were kept in our animal facility for at least 1 week before use. Mice were given water and Purina Laboratory Chow 5001 diet from Ralston Purina (St Louis, MO) ad libitum, and they were kept on a 12 h light/dark cycle.

Phosphate-buffered formalin (10%) was obtained from Fisher Scientific (Springfield, NJ).

Exposure of mice to UVB and the preparation of skin sections
The UV lamps used (FS72T12-UVB-HO; National Biological, Twinsburg, Ohio) emitted UVB (280–320 nm; 75–80% of total energy) and UVA (320–375 nm; 20–25% of total energy). There was little or no radiation <280 nm or >375 nm. The UVB dose was quantified with a UVB Spectra 305 dosimeter (Daevlin, Byran, OH). The radiation was further calibrated with a model IL-1700 research radiometer/photometer (International Light, Neburgport, MA).

Experiment 1 examined the effect of voluntary running wheel exercise on the formation of skin tumors in mice previously exposed to UVB (high-risk mice), female SKH-1 mice (10 animals/cage) were placed in transparent acrylic cages (45 x 20 x 23 cm) with corncob bedding. The mice were treated with UVB (30 mJ/cm2) 3 times/week for 16 weeks and UVB treatment was stopped. When the animal(s) developed a small skin nodule, the animal(s) was excluded from further study. The remaining treated mice without tumors and with a high risk for the development of skin tumors in the absence of continued UVB were then separated into two groups (30 mice/group and 10 animals/cage). For 14 weeks subsequent to stopping UVB exposure, one group of animals was placed into cages with running wheels (16 cm diameter, 7 cm width) with free access to the wheel 24 h/day. Another group of animals was placed into cages with no running wheels. The wheels were attached to a permanent magnetic switch that activated a digital counter to count wheel revolutions. Running wheel revolutions were recorded approximately every 12 h at the start of the light and dark cycles with total distance run per day determined by multiplying the number of wheel rotations by the circumference of the wheel.

Food and water consumption were measured every 3 days and body weights were recorded once each week. The number and size of tumors in each living animal was measured each week for 14 weeks.

Experiment 2 examined the effect of voluntary running wheel exercise on the formation of skin tumors in mice during UVB exposure (a complete carcinogenesis study). A total of 60 female SKH-1 hairless mice were divided into two groups (30 mice/group and 10 animals/cage) and placed in transparent acrylic cages (45 x 20 x 23 cm) with corncob bedding. One group of animals was placed in cages with running wheels whereas the other group had no running wheels. Mice were treated with UVB (30 mJ/cm2) 2 times/week for 33 weeks. An additional 30 female SKH-1 mice served as the no UVB light controls. These animals were divided into two groups of 15, one with access to running wheels and the other with no running wheels.

Food and water consumption was measured twice each week and body weights were recorded once each week. Running wheel revolutions were recorded approximately every 12 h at the start of the light and dark cycle. The number and size of tumors in each living animal was measured each week for 33 weeks in the UVB-treated animals. None of the non-UVB-treated animals developed a tumor.

At the completion of Experiments 1 and 2, the animals were killed and dorsal skin was removed and stapled to a plastic sheet before being placed in 10% phosphate-buffered formalin for histological examination. The parametrial fat pads were removed and weighed. The thickness of the dermal fat layer and the thickness of the dermal muscle layer at least 1 cm away from tumors were measured using an ocular micrometer with an Olympus BHTU light microscope under 100-fold magnification, and the values from 5 to 10 representative areas per mouse were averaged.

All the tumors from the animals were collected and characterized histologically as described previously (5). Tumor volume was determined by measuring the 3D size (height, length and width) of each mass. The average of the three measurements was used as the diameter. The radius (r) was determined, and the volume was calculated by: Volume = 4{pi}r3/3.

Statistical analysis
Student's t-tests were used to determine differences between running wheel treatment and no running wheel treatment on food and fluid consumption, and body weight. For the analyses of tumor-free distributions between the two treatments, the Kaplan–Meier method was used for estimations, and the log-rank test was used to test homogeneity of the distributions between the two treatments (6). The GEE (generalize estimating equation) method (7) for longitudinal data was used for analyses of the number of tumors per mouse and the total tumor volume per mouse over time between the two treatment groups. The auto-regressive correlation structure was used in the GEE analyses. In order to stabilize the variations, the square-root transformation was used for the number of tumors per mouse, and the logarithmic transformation was used for tumor volume per mouse. When the treatment and time interaction was not significant, the final model did not include the interaction term. The Pearson correlation coefficients were used for the analyses of the association between thickness of dermal fat layer and the number of tumors.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Use of the running wheel during the light and dark cycles
Animals with access to running wheels ran ~2 times as long during the dark cycle as during the light cycle. In Experiment 1, wheel revolutions were 92.06 ± 2.09/h/mouse during the light cycle and 180.31 ± 2.05/h/mouse during the dark cycle. Over the total 24 h period, wheel revolutions were 138.62 ± 1.96/h/mouse. In Experiment 2, animals with access to running wheels ran ~2 times as long during the dark cycle as during the light cycle. Wheel revolutions were 76.22 ± 2.41/h/mouse during the light cycle and 149.32 ± 1.69/h/mouse during the dark cycle. Over the total 24 h period, wheel revolutions were 110.27 ± 1.71/h/mouse. In both experiments, the distance run by mice translates to ~1 mile/mouse/day assuming that one mouse is on the running wheel and that all 10 mice shared the use of the running wheel equally. Visual observations indicate that two or three mice were often on the running wheel, indicating that the mice ran 2–3 miles/day. The number of running wheel revolutions recorded by the group exposed to UVB was not significantly different from the number of revolutions recorded by the group not exposed to UVB (no UVB control).

Effect of voluntary running wheel exercise on body weight, food and water consumption
Although there were no differences in initial or final body weights between the running wheel and no running wheel groups, animals in the running wheel group consumed 19% more food (P < 0.0001) and 23% more water (P < 0.0001) compared with animals in the no running wheel group in Experiment 1, and animals in the running wheel group consumed 25% more food (P < 0.0001) and 24% more water (P < 0.0001) compared with animals in the no running wheel group in Experiment 2 (Table I). The effects of the running wheel on food and water consumption in the animals not exposed to UVB were similar to the effects observed in the UVB-treated animals (data not shown).


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  		Table I Effect of voluntary running wheel exercise on food consumption, fluid consumption and body weight in SKH-1 mice

 
Effect of voluntary running wheel exercise on fat store and muscle mass
In Experiment 1, running wheel exercise decreased the weight of the parametrial fat pads by 41% (P < 0.0001), decreased the thickness of the dermal fat layer by 21% (P < 0.05), but the 7% increase in the thickness of the dermal muscle layer was not significant (Table II). In Experiment 2, running wheel exercise decreased the weight of the parametrial fat pads by 32% (P < 0.01), decreased the thickness of the dermal fat layer by 26% (P < 0.01), but the 9% increase in the thickness of the dermal muscle layer was not significant (Table II). In the non-UVB-exposed animals, running wheel exercise decreased the weight of the parametrial fat pads by 35% (P < 0.01), decreased the thickness of the dermal fat layer by 58% (P < 0.01) and increased the thickness of the dermal muscle layer by 18% (not statistically significant; data not shown).


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  		Table II Effect of voluntary running wheel exercise on the weight of the parametrial fat pads, the thickness of the dermal fat layer and the thickness of the dermal muscle layer in SKH-1 mice

 
Effect of voluntary running wheel exercise on the formation of skin tumors in mice previously exposed to UVB (high-risk mice)
In Experiment 1, mice were exposed to UVB light (30 mJ/cm2) 3 times/week for 16 weeks and UVB administration was stopped. These tumor-free mice were then divided into two treatment groups based on body weight. One group of mice had access to a running wheel in their cages and the other group of mice was placed in cages without a running wheel. The number and size of tumors in each animal was measured each week for 14 weeks.

The results indicated that these previously initiated animals with access to running wheels had an increased latency for the development of tumors compared with animals with no running wheels. At each time point, the tumor incidence in the running wheel group was lower than in the no running wheel group (Figure 1A). A 50% tumor incidence was seen at Week 4 in the no running wheel group, and a 50% tumor incidence was seen at Week 7 in the running wheel group. The median tumor-free time for the no wheel group was 3.5 weeks with a 95% confidence interval (CI) from 3 to 7 weeks. The median tumor-free time for the running wheel group was 7 weeks with a 95% CI from 6 to 10 weeks. The log-rank test of the homogeneity of the tumor-free distribution functions showed that the difference between the two treatment groups was statistically significant (P = 0.003) (Figure 1B). In both the no running wheel and running wheel groups, the number of tumors per mouse increased with time (Figure 1C), but throughout the 14 weeks of tumor development, animals with access to running wheels had a decreased number of tumors per mouse compared with animals with no running wheels. The interaction between treatment and time was significant (P = 0.008), indicating that the rate of increase in tumor number per mouse was different between the two groups (Figure 1D). The rate of increase in the square root of the number of tumors was 0.27/week/mouse for the no running wheel group and was 0.20/week/mouse for the running wheel group. The rate of increase for the no wheel group was statistically significantly greater than that for the running wheel group (P = 0.0052). In addition, the tumor volume per mouse increased slowly at first until a certain time point and then increased quickly in both groups (Figure 1E). At all time points, the tumor volume in the no running wheel group was greater than in the running wheel group. The variation of the tumor volume per mouse increased over time with the increase in the mean tumor volume (Figure 1F). The interaction between treatment and time was not significant (P = 0.770), indicating that the rate of increase in the tumor volume per mouse was similar in both groups. The difference in log of tumor volume per mouse between the two groups was significant (P = 0.0062). On average, the tumor volume per mouse for the no wheel group was ~5.09 times more than the tumor volume per mouse for the running wheel group. The results indicate that voluntary running wheel exercise decreased tumor size.


Figure 1
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  		Fig. 1 Effect of voluntary running wheel exercise on skin tumorigenesis versus time in initiated SKH-1 mice previously exposed to UVB (high-risk mice). SKH-1 mice (30/group; 10 animals/cage) were treated with UVB (30 mJ/cm2) 3 times/week for 16 weeks. These tumor-free mice were then divided into two groups. For 14 weeks, one group had access to a running wheel in the cage, whereas the other group had no running wheel. The number and size of tumors in each mouse was recorded once a week for 14 weeks. In (A), the percentage of mice with tumors is indicated. In (B), the tumor-free distribution function of the no running wheel and running wheel groups was evaluated (P = 0.003 for testing the difference in distributions between groups). The median tumor-free time was 3.5 weeks for the no running wheel group and 7 weeks for the running wheel group. In (C), the number of tumors per mouse was determined. In (D), the square root of the number of tumors per mouse was determined (P = 0.008 for testing the difference in rate of change between the two groups). In (E), the tumor volume per mouse was determined. In (F), the log of the tumor volume per mouse was determined (P = 0.0036 for testing the difference in the log of the tumor volume per mouse between the two groups). The log of the tumor volume per mouse was 5.09 times greater in the no running wheel group than in the running wheel group. The rate of change in tumor volume per mouse was not different between the two groups.

 
Effect of voluntary running wheel exercise on the formation of skin tumors in mice during UVB exposure (a complete carcinogenesis study)
In Experiment 2 (complete UVB-induced carcinogenesis study), one group of mice had access to running wheels whereas the other group did not; these mice were treated with UVB (30 mJ/cm2) 2 times/week for 33 weeks. The number and size of tumors in each animal was measured each week.

The results showed that mice in the no running wheel group started developing tumors 20 weeks after the start of UVB exposure whereas animals in the running wheel group started developing tumors 23 weeks after the start of UVB exposure (Figure 2A). Until the 29th week of UVB exposure, tumor incidence in the running wheel group was always lower than the no running wheel group. The median tumor-free time for the no running wheel group was 25 weeks of UVB exposure with a 95% CI from Week 24 to 26. The median tumor-free time for the running wheel group was 27 weeks of UVB exposure with a 95% CI from Week 25 to 28. The log-rank test of the homogeneity of the tumor-free distribution function showed that the difference between the two treatment groups was statistically significant (P = 0.0065) (Figure 2B). In both the no running wheel and running wheel groups, the number of tumors per mouse increased with time (Figure 2C). From the 27th week of UVB exposure to the end of 33 weeks, the difference in tumor number between the groups remained consistent. The interaction between treatment and time was significant (P = 0.0025), indicating that the rate of increase in tumor numbers per mouse was different between the two groups. The rate of increase in the square root of the number of tumors per mouse was 0.34/week for the no running wheel group and 0.29/week for the running wheel group (Figure 2D). The rate of increase in tumors/mouse for the no running wheel group was significantly greater than that for the running wheel group (P = 0.0010). The tumor volume per mouse increased over time in both groups (Figure 2E), as did the variation of the tumor volume per mouse. The interaction between treatment and time was not significant (P = 0.372), indicating that the rate of increase in the tumor volume per mouse was similar in both groups. The difference in the log of tumor volume per mouse between the two groups was significant (P = 0.0003). On average, the tumor volume per mouse for the no running wheel group was ~5.73 times more than the tumor volume per mouse for the running wheel group (Figure 2F). These results indicate that voluntary running wheel exercise decreased tumor size.


Figure 2
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  		Fig. 2 Effect of running wheel exercise on skin tumorigenesis versus time in a complete UVB-induced carcinogenesis model. SKH-1 mice (30/group; 10 animals/cage) were treated with UVB (30 mJ/cm2) 2 times/week for 33 weeks. For the entire 33 weeks, one group had access to a running wheel in the cage, whereas the other group had no running wheel. The number and size of tumors in each mouse was recorded once a week after the start of tumor development. In (A), the percentage of mice with tumors is indicated. In (B), the tumor-free distribution function of the no running wheel and running wheel groups was evaluated (P = 0.0065 for testing the difference in distributions between groups). The median tumor-free time was 5 weeks for the no running wheel group and 7 weeks for the running wheel group. In (C), the number of tumors per mouse was determined. In (D), the square root of the number of tumors per mouse was determined (P = 0.0025 for testing the rate of change between the two groups). In (E), the tumor volume per mouse was determined. In (F), the log of the tumor volume per mouse was determined (P = 0.0003 for testing the difference in the log of the tumor volume per mouse between the two groups). The log of the tumor volume per mouse was 5.73 times greater in the no running wheel group than in the running wheel group. The rate of change of tumor volume per mouse was not different between the two groups.

 
All histopathological examinations were done blinded and revealed that voluntary running wheel exercise significantly decreased the number of non-malignant tumors (primarily keratoacanthomas) as well as malignant tumors. Voluntary running wheel exercise decreased the number of non-malignant tumors per mouse by 34% in both experimental models (Table III). Interestingly, running wheel exercise substantially decreased the size of non-malignant tumors and malignant tumors. Running wheel exercise decreased the total volume of non-malignant tumors per mouse by 54% in Experiment 1 and by 75% in Experiment 2. The total volume of squamous cell carcinomas per mouse decreased by 73% in Experiment 1, and by 69% in Experiment 2 (Table IV).


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  		Table III Effect of voluntary running wheel exercise on the formation of histologically characterized skin tumors in UVB-treated SKH-1 mice

 

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  		Table IV Effect of voluntary running wheel exercise on the size of histologically characterized skin tumors in UVB-initiated SKH-1 mice

 
Relationship between the thickness of dermal fat and the number of tumors per mouse
The thickness of dermal fat layer was found to be associated with the number of tumors. In Experiment 1, the correlation coefficient (r = 0.33) between the thickness of the dermal fat layer and the number of tumors per mouse was statistically significant (P < 0.01) (data not shown). In Experiment 2, the correlation coefficient (r = 0.38) between the thickness of the dermal fat layer and the number of tumors per mouse was statistically significant (P < 0.01; Table V). On average, in both experiments, as the thickness of dermal fat layer increased, the number of tumors per mouse increased.


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  		Table V Relationship between the thickness of the dermal fat layer away from tumors and the number of tumors/mouse in mice with a running wheel or without a running wheel

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the present study, we found that voluntary running wheel exercise following UVB exposure in high-risk mice and voluntary running wheel exercise during UVB exposure in a complete carcinogenesis study decreased tumor incidence, decreased number of tumors per mouse and decreased tumor volume per mouse. Although there were no differences in body weight between mice with access to running wheels and mice without running wheels, at the end of both studies mice with access to running wheels consumed significantly more food and water but had decreased parametrial fat pad weight, decreased dermal fat layer thickness and increased dermal muscle layer thickness, compared with animals without running wheels. These studies provide additional data for a relationship between decreased body fat and decreased skin tumorigenesis. Evidence for an association between decreased body fat and decreased tumor formation has been shown previously in an earlier study where animals were treated with tea or caffeine (3). Decreased parametrial fat pad weight and decreased thickness of the dermal fat layer away from tumors and directly under tumors was associated with decreased tumor number (3).

However, how decreased body fat or increased exercise may inhibit carcinogenesis is poorly understood. Preliminary mechanistic studies in our laboratory indicated that voluntary running wheel exercise stimulated the UVB-induced increase in apoptosis in epidermis as well as apoptosis in skin tumors. It is likely that these effects contribute to the inhibitory effect of voluntary exercise on UVB-induced carcinogenesis. The results of our studies are important since the relationship between skin carcinogenesis and increased activity by voluntary running wheel exercise has not been studied previously.

In humans, obesity has been associated with some cancers (8). Many studies on the potential health benefits of exercise have focused on circulatory disorders and related changes in plasma lipoproteins (9) longevity (10,11), enhanced immune functions (12) and lower sex hormone levels (13). Epidemiological evidence has revealed an inverse relationship such that increased physical activity is associated with decreased incidence and/or mortality rates for various cancers. The relationship appears strongest for colorectal cancer (14,15), prostate cancer (16) and female estrogen-dependent cancers of the breast, ovary and endometrium (17). Out of 16 studies on recreational exercise 11 reported a 12–60% decrease in risk of breast cancer (18). Leanness and physical activity have been consistently associated with a reduced risk for colorectal cancer in both men and women. Although recent studies have found inhibitory effects of exercise on colon and breast carcinogenesis, little research has evaluated the effects of exercise on skin carcinogenesis. A case–control study (19) examined the risk of melanoma associated with exercise and concluded that men and women exercising 5–7 days/week were at a decreased risk of melanoma. Data from two recent case–control studies in the Netherlands (20) and Switzerland (21,22), and a cohort study in the USA (23) suggest that physical activity at any age is beneficial for reducing cancer risk.

Experimental studies performed in animals suggest that chronic exercise, especially when performed prior to tumorigenesis, can retard, delay or prevent the incidence, progression or spread of experimental tumors. In an azoxymethane-induced colon carcinogenesis model, tumor incidence and number of tumors per animal were inhibited in male F344 rats with access to running wheels (24). Voluntary running wheel exercise also reduced breast tumor yields and delayed the time of appearance of these tumors in female F344 rats treated with N-nitrosomethylurea (25). The question of stress-induced versus voluntary exercise may also play a role in tumor formation. For instance, in mammary carcinogenesis, forced exercise on a treadmill increased 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor response in female Sprague–Dawley rats fed a high-fat diet, as compared with those not exercised (26) whereas voluntary exercise reduced N-nitrosomethylurea-induced mammary tumorigenesis in female rats fed a high-fat diet (27). Additionally, exhaustive swimming exercise in untrained rats treated with a colon carcinogen increased the number of aberrant crypt foci when compared with the non-exercised group (28). Thus, it appears that the type, duration and intensity of exercise could be protective or increase the risk.

Finally, since our mice were housed 10 animals/cage (to increase our ‘N’), we could not determine how much each individual mouse ran each day. Visual observation indicated that up to four mice could run on the running wheel together. Assuming the reduction in body fat reflects increased exercise, the inverse relationship between thickness of the dermal fat layer and tumor formation indicates that those mice that ran more had fewer tumors.

In summary, our results suggest that voluntary running wheel exercise inhibits UVB-induced skin carcinogenesis in UVB-initiated high-risk mice and in mice continually exposed to UVB (complete carcinogenesis model). Voluntary running wheel exercise decreased tumor incidence, decreased tumor number and decreased tumor size compared with animals without running wheels. In addition, running wheel exercise decreased the weight of the parametrial fat pads, decreased the thickness of the dermal fat layer and increased the thickness of the dermal muscle layer.


   Notes
 
{dagger}These authors should be considered co-first authors. Back


   Acknowledgments
 
We thank Ms. Florence Florek for her excellent assistance in the preparation of this manuscript. This study was supported in part by NIH Grants ES05022, ES007148, CA80759 and CA88961 as well as a State of New Jersey Commission on Cancer Research Grant 05-1976-CCR-EO.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received November 2, 2005; revised April 2, 2006; accepted April 11, 2006.


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