Influence of Exercise on Inflammation in Cancer
Influence of Exercise on Inflammation in Cancer
Adiposity, energy balance, insulin, adipokines, estrogen, and immune function all have been reported to affect the tumorigenic response and are known to be altered by physical activity. Interestingly, these factors have been shown to influence the inflammatory response and may support a possible indirect effect of physical activity on inflammatory processes in cancer.
Both the animal and epidemiological literature supports an association between obesity and cancer risk; this relationship is particularly strong for colon cancer and for postmenopausal breast cancer. We have reported previously that the high-fat diet–induced increase in body weight, body fat percent, and fat mass in the ApcMin/+ mouse is associated with an increase in the number of large polyps.
A likely contributor to the benefits of exercise on cancer risk is alterations in body composition and specifically a reduction in fat mass. In a rodent study, we reported an exercise-induced reduction in body weight in a mouse model of breast cancer, and this was consistent with a decrease in tumor number and volume. Although we did not explore the relative importance of changes in body composition on cancer progression, the findings support a potential role for reduced body weight as a possible contributing factor for the deceased tumor burden. Furthermore, we recently reported a significant decrease in waist-to-hip ratio in a population of obese individuals after a 1-yr diet and physical activity intervention. Importantly, in both of the aforementioned studies, we report a decrease in circulating inflammatory mediators that may be linked to the exercise-induced changes in body composition. Given the strong associations between obesity and cancer risk, a physical activity–induced decrease in adiposity is a very likely contributor to the benefits of exercise on tumorigenic responses and may influence the reported antiinflammatory effects of exercise in cancer models.
The concept of energy balance, whether an individual consumes and expends the same amount of energy, has been associated with disease risk, including cancer. Energy balance has become an important concept in the etiology of cancer given its association with adiposity and adiposity-related inflammation. Thus, high-energy intake may increase the risk of colon and breast cancers, whereas high-energy expenditure has been associated with a reduced risk.
Energy is expended through the basal metabolic rate, the thermic effect of digesting food, and physical activity. Thus, increasing energy expenditure through physical activity is likely to decrease cancer risk. As elimination of excess fat is linked to a decrease in proinflammatory cytokines, this process will result almost certainly in decreased inflammation. Using a rat model of chemically induced breast carcinogenesis, the effects of diet restriction and different intensities of wheel-running activity were compared to examine the effects of limiting energy availability on breast cancer. The energetics interventions inhibited the carcinogenic response, resulting in a reduction in cancer incidence, multiplicity, and burden, which was associated with a decrease in inflammatory cytokines. However, given the broad pleotropic effects of exercise, it is difficult to independently attribute energy expenditure to the findings on carcinogenesis and inflammation. Nonetheless, energy expenditure through physical activity is likely to influence cancer risk, which may be mediated through a reduction in inflammatory processes.
Imbalances in metabolic mediators have been linked to a heightened risk for cancer. Evidence indicates that insulin resistance and its accompanying pathological conditions are associated with various cancers. Interestingly, there is now evidence to suggest that insulin resistance may even promote inflammation. Thus, improvements in insulin signaling may decrease inflammation.
Aerobic activity is known widely to improve metabolic outcomes including insulin resistance, fasting blood glucose and insulin, and insulin-like growth factors (IGF) and their binding proteins. A recent study reported that IGF-1 levels are lowered and specifically the IGF/IGFB3 ratio in a carcinogenic mouse model of colon cancer, which was associated with decreased tumorigenesis. Similarly, Zhu et al. reported a decrease in IGF-1 and IGFB3 levels after wheel running in rats exposed to a breast cancer carcinogen, which interestingly were associated with a decrease in inflammatory mediators. Of the biomarkers measured, the IGF/IGFBP3, IGF-1, and IGFBP3 levels were considered to be of great value in predicting cancer outcomes, along with the adipokines. Given the ability of physical activity to improve insulin-related biomarkers, it is likely that these factors contribute to the benefits of exercise on cancer risk that may be linked to reduced inflammation.
Adipose-derived hormones (adipokines) have been identified as potential mediators of the effects of exercise on cancer risk. Adiponectin has been reported to be associated negatively with cancer risk, whereas leptin has been linked to increased risk for cancer. Both of these adipokines are known to be influenced by exercise and thus have the potential to play a role in exercise-induced modulation of tumorigenic responses. Furthermore, there is evidence to support a link between adipokines and inflammation in cancer models.
Several studies have examined the benefits of exercise on adiponectin in the settings of breast cancer, whereas investigations in colon cancer virtually are nonexistent. In a rat model of breast cancer, increased adiponectin was associated with reduced tumor burden after wheel-running activity. Inflammatory outcomes also were reported to be decreased in this study. In a pilot study of breast cancer survivors, a decrease, albeit nonsignificant, in adiponectin was found after a 3-month physical activity intervention. For leptin, Colbert et al. reported an increase in leptin, which was associated with a reduced polyp number in male ApcMin/+ mouse. Furthermore, leptin has been implicated as an important biomarker in predicting the carcinogenic response after wheel running in a rat model of breast cancer. Based on the available evidence, it is clear that adipokines are linked to the tumorigenic response and even possible that modulation of the adipokine profile via physical activity may lead to a reduction in inflammatory processes.
There is a large literature base dedicated to the investigation into the role of estrogen on various cancers. In general, higher levels of endogenous estrogens are associated with an increased risk for postmenopausal breast cancer. The data for colon cancer risk are less clear; although some studies have implicated estrogen as being protective in colon cancer, others have suggested it to be an independent risk factor. Estrogen also has been implicated in the regulation of inflammatory processes, although its role remains somewhat controversial.
A recent review examined the current literature on the benefits of physical activity on reducing estradiol in postmenopausal women. Of the nine randomized controlled trials evaluated, exercise interventions were associated with approximately 10% decrease in estradiol. Despite this decrease, statistically significant effects were not reported for all studies. Nonetheless, the evidence for a reduction in estrogen with exercise is strong and may pose as a potential mechanism for the benefits of exercise in postmenopausal breast cancer. Given the inconsistencies in the colon cancer literature, it is unclear what, if any, role estrogen may play in the benefits of physical activity in colon cancer. Furthermore, although estrogen is known to influence inflammation, any interaction between physical activity, estrogen, and inflammation in relation to tumorigenesis remains to be elucidated.
Immune evasion is an emerging hallmark of cancer. A competent immune system is necessary not only for prevention of cancer development but also to slow its progression. This has led to a large body of research devoted to investigating immunotherapy for cancer. Interestingly, physical activity has been reported to enhance immune function and thus may be a potential mechanism for its benefits on cancer risk. As inflammation is an important aspect of the immune response, it is likely to be altered with changes in immune function.
We previously have reported a benefit of exercise on immune function in various mouse models, including cancer models. For example, we have shown that moderate exercise can increase the cytotoxicity of macrophages to B16 melanoma cells and decrease their metastatic spread in vivo. Similarly, we have reported an increase in natural killer cell activity with moderate exercise training. Thus, immune system alterations with exercise are likely to be a contributing factor in reducing cancer risk.
Given the broad pleotrophic effects of physical activity, other factors also likely are to play a role in the benefits of exercise on tumorigenesis. For example, it has been postulated that the exercise-induced production of novel myokines such as secreted protein acidic and rich in cysteine (SPARC) can alter the mechanisms involved in cancer pathogenesis. A recent study reported that low-intensity exercise reduced aberrant crypt foci growth in a chemically induced mouse model of colorectal cancer. However, these effects were lost in SPARC-deficient mice, implicating a role of this myokine on the benefits of exercise in colorectal cancer. Furthermore, exercise enhanced apoptosis in colon mucosal cells, but again, these effects were not evident in SPARC-deficient mice. Furthermore, in a prostate cancer model, it has been reported that exercise can alter genes responsible for metastatic dissemination in the primary tumor with a shift toward a suppression of distant metastasis. These reports provide further evidence for the complexity of the interaction between physical activity and cancer risk.
Interrelated Mechanisms for Benefits of Physical Activity in Cancer
Adiposity, energy balance, insulin, adipokines, estrogen, and immune function all have been reported to affect the tumorigenic response and are known to be altered by physical activity. Interestingly, these factors have been shown to influence the inflammatory response and may support a possible indirect effect of physical activity on inflammatory processes in cancer.
Adiposity
Both the animal and epidemiological literature supports an association between obesity and cancer risk; this relationship is particularly strong for colon cancer and for postmenopausal breast cancer. We have reported previously that the high-fat diet–induced increase in body weight, body fat percent, and fat mass in the ApcMin/+ mouse is associated with an increase in the number of large polyps.
A likely contributor to the benefits of exercise on cancer risk is alterations in body composition and specifically a reduction in fat mass. In a rodent study, we reported an exercise-induced reduction in body weight in a mouse model of breast cancer, and this was consistent with a decrease in tumor number and volume. Although we did not explore the relative importance of changes in body composition on cancer progression, the findings support a potential role for reduced body weight as a possible contributing factor for the deceased tumor burden. Furthermore, we recently reported a significant decrease in waist-to-hip ratio in a population of obese individuals after a 1-yr diet and physical activity intervention. Importantly, in both of the aforementioned studies, we report a decrease in circulating inflammatory mediators that may be linked to the exercise-induced changes in body composition. Given the strong associations between obesity and cancer risk, a physical activity–induced decrease in adiposity is a very likely contributor to the benefits of exercise on tumorigenic responses and may influence the reported antiinflammatory effects of exercise in cancer models.
Energy Balance
The concept of energy balance, whether an individual consumes and expends the same amount of energy, has been associated with disease risk, including cancer. Energy balance has become an important concept in the etiology of cancer given its association with adiposity and adiposity-related inflammation. Thus, high-energy intake may increase the risk of colon and breast cancers, whereas high-energy expenditure has been associated with a reduced risk.
Energy is expended through the basal metabolic rate, the thermic effect of digesting food, and physical activity. Thus, increasing energy expenditure through physical activity is likely to decrease cancer risk. As elimination of excess fat is linked to a decrease in proinflammatory cytokines, this process will result almost certainly in decreased inflammation. Using a rat model of chemically induced breast carcinogenesis, the effects of diet restriction and different intensities of wheel-running activity were compared to examine the effects of limiting energy availability on breast cancer. The energetics interventions inhibited the carcinogenic response, resulting in a reduction in cancer incidence, multiplicity, and burden, which was associated with a decrease in inflammatory cytokines. However, given the broad pleotropic effects of exercise, it is difficult to independently attribute energy expenditure to the findings on carcinogenesis and inflammation. Nonetheless, energy expenditure through physical activity is likely to influence cancer risk, which may be mediated through a reduction in inflammatory processes.
Insulin
Imbalances in metabolic mediators have been linked to a heightened risk for cancer. Evidence indicates that insulin resistance and its accompanying pathological conditions are associated with various cancers. Interestingly, there is now evidence to suggest that insulin resistance may even promote inflammation. Thus, improvements in insulin signaling may decrease inflammation.
Aerobic activity is known widely to improve metabolic outcomes including insulin resistance, fasting blood glucose and insulin, and insulin-like growth factors (IGF) and their binding proteins. A recent study reported that IGF-1 levels are lowered and specifically the IGF/IGFB3 ratio in a carcinogenic mouse model of colon cancer, which was associated with decreased tumorigenesis. Similarly, Zhu et al. reported a decrease in IGF-1 and IGFB3 levels after wheel running in rats exposed to a breast cancer carcinogen, which interestingly were associated with a decrease in inflammatory mediators. Of the biomarkers measured, the IGF/IGFBP3, IGF-1, and IGFBP3 levels were considered to be of great value in predicting cancer outcomes, along with the adipokines. Given the ability of physical activity to improve insulin-related biomarkers, it is likely that these factors contribute to the benefits of exercise on cancer risk that may be linked to reduced inflammation.
Adipokines
Adipose-derived hormones (adipokines) have been identified as potential mediators of the effects of exercise on cancer risk. Adiponectin has been reported to be associated negatively with cancer risk, whereas leptin has been linked to increased risk for cancer. Both of these adipokines are known to be influenced by exercise and thus have the potential to play a role in exercise-induced modulation of tumorigenic responses. Furthermore, there is evidence to support a link between adipokines and inflammation in cancer models.
Several studies have examined the benefits of exercise on adiponectin in the settings of breast cancer, whereas investigations in colon cancer virtually are nonexistent. In a rat model of breast cancer, increased adiponectin was associated with reduced tumor burden after wheel-running activity. Inflammatory outcomes also were reported to be decreased in this study. In a pilot study of breast cancer survivors, a decrease, albeit nonsignificant, in adiponectin was found after a 3-month physical activity intervention. For leptin, Colbert et al. reported an increase in leptin, which was associated with a reduced polyp number in male ApcMin/+ mouse. Furthermore, leptin has been implicated as an important biomarker in predicting the carcinogenic response after wheel running in a rat model of breast cancer. Based on the available evidence, it is clear that adipokines are linked to the tumorigenic response and even possible that modulation of the adipokine profile via physical activity may lead to a reduction in inflammatory processes.
Estrogen
There is a large literature base dedicated to the investigation into the role of estrogen on various cancers. In general, higher levels of endogenous estrogens are associated with an increased risk for postmenopausal breast cancer. The data for colon cancer risk are less clear; although some studies have implicated estrogen as being protective in colon cancer, others have suggested it to be an independent risk factor. Estrogen also has been implicated in the regulation of inflammatory processes, although its role remains somewhat controversial.
A recent review examined the current literature on the benefits of physical activity on reducing estradiol in postmenopausal women. Of the nine randomized controlled trials evaluated, exercise interventions were associated with approximately 10% decrease in estradiol. Despite this decrease, statistically significant effects were not reported for all studies. Nonetheless, the evidence for a reduction in estrogen with exercise is strong and may pose as a potential mechanism for the benefits of exercise in postmenopausal breast cancer. Given the inconsistencies in the colon cancer literature, it is unclear what, if any, role estrogen may play in the benefits of physical activity in colon cancer. Furthermore, although estrogen is known to influence inflammation, any interaction between physical activity, estrogen, and inflammation in relation to tumorigenesis remains to be elucidated.
Immune Function
Immune evasion is an emerging hallmark of cancer. A competent immune system is necessary not only for prevention of cancer development but also to slow its progression. This has led to a large body of research devoted to investigating immunotherapy for cancer. Interestingly, physical activity has been reported to enhance immune function and thus may be a potential mechanism for its benefits on cancer risk. As inflammation is an important aspect of the immune response, it is likely to be altered with changes in immune function.
We previously have reported a benefit of exercise on immune function in various mouse models, including cancer models. For example, we have shown that moderate exercise can increase the cytotoxicity of macrophages to B16 melanoma cells and decrease their metastatic spread in vivo. Similarly, we have reported an increase in natural killer cell activity with moderate exercise training. Thus, immune system alterations with exercise are likely to be a contributing factor in reducing cancer risk.
Other Factors
Given the broad pleotrophic effects of physical activity, other factors also likely are to play a role in the benefits of exercise on tumorigenesis. For example, it has been postulated that the exercise-induced production of novel myokines such as secreted protein acidic and rich in cysteine (SPARC) can alter the mechanisms involved in cancer pathogenesis. A recent study reported that low-intensity exercise reduced aberrant crypt foci growth in a chemically induced mouse model of colorectal cancer. However, these effects were lost in SPARC-deficient mice, implicating a role of this myokine on the benefits of exercise in colorectal cancer. Furthermore, exercise enhanced apoptosis in colon mucosal cells, but again, these effects were not evident in SPARC-deficient mice. Furthermore, in a prostate cancer model, it has been reported that exercise can alter genes responsible for metastatic dissemination in the primary tumor with a shift toward a suppression of distant metastasis. These reports provide further evidence for the complexity of the interaction between physical activity and cancer risk.
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