Influence of Exercise on Inflammation in Cancer

Direct Effect or Innocent Bystander?

E. Angela Murphy; Reilly T. Enos; Kandy T. Velázquez

Disclosures

Exerc Sport Sci Rev. 2015;43(3):134-142. 

In This Article

Benefits of Physical Activity on Cancer

Although not all, the majority of literature supports a beneficial effect of various modes of physical activity on cancer risk. A preponderance of this evidence comes from observational epidemiological studies and controlled experiments in rodent models.

Colon Cancer

Colon cancer is the third most common malignancy and the fourth most common cause of cancer mortality, identifying it as a significant global health concern. Physical inactivity has been reported to account for a substantial number of all colon cancer cases, whereas physical activity has been associated with a reduced risk. In fact, it has been estimated that high levels of physical activity may reduce the risk for colon cancer by as much as 50%. This presents an enormous potential for chemoprevention.

The majority of physical activity studies in rodents have used the ApcMin/+ mouse model of intestinal tumorigenesis, arguably the most widely used genetic mouse model for cancer studies that involve the gastrointestinal tract. Colbert et al.[6] examined possible sex-specific differences for physical activity using this model and found a decrease in polyp development in male, but not female, mice after 8 wk of treadmill running. More recently, Mehl et al. examined the influence of exercise mode on tumorigenesis in the ApcMin/+ mouse by comparing treadmill running with wheel running using both male and female mice. It was reported that 9 wk of treadmill running decreased total intestinal polyps as well as the number of large polyps in male runners but, consistent with the findings of Colbert et al., there was no benefit of treadmill running in female mice and no influence of wheel running on tumorigenesis in either sex.[3] Data from our laboratory partially support this result as we have reported a decrease in the number of large polyps (>2 mm) after treadmill exercise in male mice but no change in total polyp number (Fig. 1A, B). Similar results were reported by Basterfield and Mathers[5] who found a decrease in the number of large polyps after 10 to 12 wk of treadmill exercise but not for wheel running. These findings for a benefit of treadmill running on tumorigenesis in the ApcMin/+ mouse were corroborated in a chemically induced (azoxymethane) mouse model of colon cancer; it was reported that 6 wk of treadmill exercise suppressed the generation of aberrant crypt foci in the colon.[1] However, in contrast to the findings of Baltgalvis et al.[3] and Basterfield and Mathers,[5] a recent study reported that voluntary exercise did reduce the number of intestinal tumors in ApcMin/+ as well as azoxymethane/dextran sodium sulfate–treated mice.[20]

Figure 1.

Effects of treadmill exercise on colon cancer and breast cancer in mice. Differences in polyp number (A) and polyp size distribution (B) were examined in sedentary (Sed) and exercised (Ex) Apc Min/+ mice (n = 6–9 per group) at 16 wk of age. [Adapted from (25). Copyright © 2014 International Journal of Oncology. Used with permission.] Differences in tumor number (C) and volume (D) were examined in sedentary (Sed) and exercised (Ex) C3(1)TagSV40 mice across time (n = 12–14 per group). [Adapted from (28). Copyright © 2011 Elsevier. Used with permission.] Values are means ± SEM. *Significant difference (P < 0.05).

Based on the available animal literature, it seems that physical activity is effective at reducing tumor size, multiplicity, or both in most, but not all, studies. Furthermore, treadmill running seems to be a more efficient mode of exercise than wheel running for reducing colon tumorigenesis. This effect likely is to be attributed, at least in part, to differences in the intensity of the exercise; although, in general, mice in activity wheels run longer distances compared with their treadmill-running counterparts, the exercise intensity tends to be greater with treadmill running. In the study by Baltgalvis et al.,[3] wheel runners ran approximately three times more than treadmill runners but only treadmill running reduced polyp number. Another possible explanation for this disparity could be changes in energy balance. In the same study, wheel runners consumed approximately 25% more food than the control mice, whereas there was no difference in calorie consumption of treadmill mice, placing them in a state of negative caloric balance,[3] which is known to decrease tumorigenesis. Interestingly, there may be interactions between physical activity and sex in the ApcMin/+ mouse because several studies have reported the benefits of physical activity in male but not female mice.[3,6] However, the mechanisms for these effects were not explored in the aforementioned investigations. Although estrogen may be an obvious potential mechanism, as it stands, its role in colon cancer is unclear; some studies have implicated estrogen as being protective in colon cancer whereas others have suggested it to be an independent risk factor. Thus, this makes it difficult to speculate on any interaction between physical activity and estrogen in colon cancer. Nonetheless, the current literature indicates that sex is an important factor when investigating the effects of physical activity on tumorigenesis, at least in the ApcMin/+ mouse.

The human data mostly have mirrored the animal findings. In the Melbourne Collaborative Cohort Study, a prospective cohort study of 41,528 Australians, participants with incident cases of colorectal cancer were interviewed about their physical activity. Among the 526 identified cases of colorectal cancer, those who had engaged in physical activity had an improved disease-specific survival.[15] Similarly, a recent study in a multiethnic colon cancer screening population of 982 patients examined the relationship between exercise and the prevalence of polyps. It was reported that exercising for 1 h wk−1 or more was associated with a lower prevalence of polyps and adenomas when compared with those who exercised less or not at all.[33] Although the majority of the literature supports an inverse correlation between physical activity and colon cancer risk, there is a literature base that has failed to report a relationship. For instance, Meyerhardt et al.[26] examined colorectal cancer–specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis by a prospective observational study of 573 women with stage I to III colorectal cancer. It was reported that prediagnosis physical activity was not predictive of mortality.[26] Interestingly, however, increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality.[26] To address the inconsistencies in human literature, a recent meta-analysis of seven prospective cohort studies was performed. It was concluded that physical activity, both prediagnosis and postdiagnosis, is associated with better prognosis of colorectal cancer.[17]

Although animal data and epidemiological literature largely support an inverse relationship between physical activity and risk for colon cancer, there is an overall lack of clear evidence on the specific details underlying the optimal mode, intensity, and duration of exercise, which may explain the inconsistencies across studies. Furthermore, studies using a randomized controlled trial design to determine the benefits of physical activity in patients with colorectal cancer currently are nonexistent.

Breast Cancer

Breast cancer currently is the second most commonly diagnosed cancer and the leading cause of cancer-related death in women in the United States. Undoubtedly, there is an underlying genetic origin to certain breast cancer cases. However, many, and perhaps the majority of incidents, are linked to behavioral or lifestyle risk factors. Accumulating epidemiological evidence, as well as controlled experimental studies using mouse models, indicates a relationship between physical activity and reduced breast cancer risk.

The most common rodent model used in physical activity prevention studies has been chemically induced mammary tumorigenesis (e.g., 7,12-dimethylbenzanthracene, N-nitrosomethylurea). A large body of this work has been done by Zhu et al.,[38] whose work has demonstrated convincingly that voluntary wheel-running activity is effective at reducing breast cancer incidence, multiplicity, and burden. However, although the majority of studies have reported a positive influence of exercise training on tumor number, growth, and incidence using chemically induced models, there also have been a number of studies that have reported negative findings. Genetically engineered mouse models to study the relationship between exercise and breast cancer risk have been used in several recent studies; these models are thought to mimic the spontaneous development of breast cancer in humans more closely. We used the C3(1)SV40Tag mouse model of breast cancer to examine the effects of exercise on mammary tumorigenesis. Our initial study incorporated a treadmill-running protocol where we reported a reduction in tumor number and volume with exercise[28] (Fig. 1C, D). We followed this up with a second study to examine the influence of voluntary wheel-running activity on mammary tumorigenesis using the same mouse model. Voluntary wheel running reduced tumor volume per tumor (~40%) but interestingly was associated with increased tumor number.[34] To our knowledge, there have been only two other studies that have examined the effects of exercise on breast cancer using genetically engineered mouse models.[7,12] Goh et al.[12] examined the effects of voluntary wheel running on tumor progression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Voluntary wheel running significantly reduced tumor sizes compared with nonrunners after 3 wk of running, and the distance run was correlated negatively with tumor size.[12] On the contrary, Colbert et al.[7] reported a detrimental effect of both treadmill and wheel-running activity on mammary tumorigenesis in a p53-deficient (p53+/-):MMTV-Wnt-1 mouse model of breast cancer. Treadmill running increased the rate of tumor development and the proportion of mice with multiple carcinomas and decreased survival time, whereas wheel running resulted in an increased incidence and multiplicity of mammary carcinomas,[7] which may have resulted from an exercise-induced increase in the expression of the Wnt-1 transgene or an interaction between p53 dosage and exercise.[7]

In general, the majority of the available animal data support the notion that physical activity decreases the risk for breast cancer. Furthermore, it seems that increasing exercise intensity enhances the likelihood of inhibiting tumorigenesis, whereas lower exercise intensities result in inhibition, no effect, or enhancement of a tumorigenic response. Most of the data supporting these conclusions come from studies using chemically induced mammary tumorigenesis where any reported inconsistencies likely are caused by methodological issues with respect to the dose, timing, route, and type of carcinogen. This is not surprising given the relative dearth of studies using transgenic animals; appropriate transgenic models for exercise studies have yet to be considered extensively as to date only three models, which have resulted in inconsistent findings, have been used.

There have been a large number of epidemiological investigations that have explored the relationship between breast cancer and physical activity. On average, a 25% reduction in breast cancer risk for physically active women compared with the least active women has been estimated. These associations appeared to be the strongest for recreational activity, activity sustained across the lifetime or done after menopause, and activity that is of moderate to vigorous intensity and performed regularly. For example, the relationship between physical activity and breast cancer risk was evaluated in 3424 women of the French E3N cohort. A linear decrease in the risk of breast cancer was observed with increasing amounts of moderate and vigorous recreational activities.[36] Similarly, using NHANES data, it was found that moderate- to vigorous-intensity activity has significant inverse associations with biomarkers associated with breast cancer risk, whereas sedentary time may contribute independently to breast cancer risk.[22] Furthermore, there is a growing body of literature that supports an improved overall and breast cancer–specific survival for women who are physically active. In one study, a cohort of 1231 women diagnosed with breast cancer was followed for a minimum of 8.3 yr for any cancer progression and a minimum of 10.3 yr for deaths.[10] Both moderate- and vigorous-intensity activity decreased the risk of breast cancer death and moderate-intensity activity decreased the risk of a recurrence, progression, or new primary cancer.[10] Of further significance is the emerging evidence that supports a benefit of physical activity on the side effects of anticancer therapy, radiation, surgery, and recovery after chemotherapy; in general, physical activity has been reported to increase quality of life during various breast cancer treatment regimens.

Based on the epidemiological evidence, it is clear that moderate to vigorous activity provides the greatest benefit to breast cancer risk and breast cancer–specific survival. However, specific details on the optimal mode, intensity, and duration of exercise as well as the timing of exercise in relation to menopause are still lacking. Furthermore, there is a clear need for randomized controlled trials to substantiate the findings reported in the epidemiological and animal literature.

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