Physical Activity and Its Effects on Prostate Cancer
Physical Activity and Its Effects on Prostate Cancer
Although the precise biological mechanisms are not yet understood, it is postulated that physical activity may reduce the risk of prostate cancer directly or indirectly via inter-related biological pathways (Figure 1). Direct protective effects of physical activity may be mediated by proteins secreted by the skeletal muscles (myokines). Indirect protective effects may be due to the decrease in adiposity, changes in sexual and metabolic hormones, reduction of inflammation and improvement of immune function.
(Enlarge Image)
Figure 1.
Hypothesized mechanisms linking physical activity to prostate cancer risk. Physical activity might decrease risk of prostate cancer via different biological mechanisms (adapted from McTiernan).
The mechanisms linking physical activity to prostate cancer biology have not been fully elucidated. From the papers listed in Table 3 , a number of observations can be made. First, vigorous physical activity upregulates cell cycling and DNA repair pathways and modulates canonical pathways involved in cell signaling and metabolism and Nrf2-mediated oxidative stress response. Second, a number of studies have demonstrated slowed growth and increased apoptosis of LNCaP cells incubated with exercise serum following acute exercise, from those with high levels of physical activity and following a diet and exercise intervention. Mechanistically, there was evidence that these effects were attributable to increased levels of tumor-suppressor proteins such as insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-3, p53, p21 and caspases and decreased levels of tumor-promoting proteins Bcl-2, epidermal growth factor and insulin-like growth factor 1 (IGF-1). There was also evidence of a direct and indirect reduction in inflammation via lower nuclear factor-κB activation in LNCaP cells incubated with postexercise serum. Aerobic exercise training can also decrease IGFPB-3 and increase the IGF-1/IGFBP-3 ratio. In this study, increases in aerobic fitness correlated with favorable levels of leptin and favorable leptin:adiponectin and IGF-1:IGFBP-3 ratios at 3 and 6 months into training. Third, acute to chronic moderate to high intensity aerobic physical activity alters sexual hormones and their receptors. It reduces PSA and androgen receptor expression and increases corticosterone plasma, dihydrotestosterone, testosterone and estrogen receptor α and β expression. The reduction in PSA levels might be through white blood cell modulation. Fourth, physical activity of different intensities reduces inflammation by altering C-reactive protein, interleukin 6 (IL-6), tissue necrosis factor alpha, albumin, fibrinogen, white blood cells and factor VIII activity. These studies suggest that leisure time physical activity may elicit changes to factors which may reduce the risk of prostate cancer by reducing inflammation in young and older adults. Fifth, physical activity induces synergistic effects through oxidative stress modulation. Four weeks of treadmill running in rats reduces prostate tumor proliferation, Bcl-2 expression in tumors, enzymatic antioxidant defense in muscle and thiobarbituric acid reactive substances and 8-oxo-7,8-dihydro-2′-deoxyguanosine levels in tumor. Sixth, physical activity modulates the microenvironment of the tumor by altering the tumor microvascular oxygenation, hypoxia and vascular function. Treadmill training in rats over 5–7 weeks increased tumor microvascular Po2 and reduced tumor hypoxia. Finally, in a series of animal studies, weeks of treadmill running altered inflammatory markers IL-6 and macrophage chemoattractant protein-1, tumor-promoting factors hypoxia-inducible factor 1α and vascular endothelial growth factor and tumor-suppressor proteins caspase-3, humoral and apoptotic factors, which influence the development and progression of prostate cancer.
Where all these studies demonstrate a biological influence of physical activity there is no consensus on the level of activity that is required to change a specific cellular pathway or functional endpoint. The studies have varied frequency, duration and intensity of the physical activity. In addition, each individual participant may respond differently to the physical activity intervention. We propose that a better way of demonstrating the beneficial effects of physical activity is by correlating them to a biological endpoint (that is, a change in a signaling pathway) with a functional outcome (that is, regression of a tumor) rather than the intervention. However, these results suggest that physical activity might reduce the risk of prostate cancer by favorably altering the immune function and signaling pathways relevant to carcinogenesis of the prostate.
The skeletal muscle has been identified as an active endocrine organ that produces, expresses and releases proteins (myokines). One cause of the production, expression and release of myokines by the skeletal muscle fibers is physical activity, particularly the one involving the contraction of skeletal muscles such as resistance exercise. The effects of physical activity might be transmitted through myokines by affecting body homeostasis. Through the myokine signaling, skeletal muscles can communicate with other organs that could underlie effects of physical activity on systemic health.
The adipose tissue is an endocrine organ that secretes various proteins (adipokines), such as adipsin, leptin and adiponectin. Adiponectin is the only antiangiogenic, antimitogenic and anti-inflammatory adipokine. Although physical activity and muscle mass have a greater effect on insulin kinetics than physical activity and fat mass, physical activity decreases body weight and reduces abdominal fat (adiposity) that alters insulin metabolism. This in turn alters insulin metabolism, which in turn alters blood glucose IGF-1, IGFBP, sex hormones and sex hormone-binding globulin (SHBG). Reducing adiposity alters the levels of adipokines by increasing adiponectin and reducing the proinflammatory adipokines. In addition, physical activity might alter adipose tissue DNA methylation potentially affecting adipocyte metabolism, which might alter adipokine levels, the IGF axis and tumor-suppressor proteins.
Myokines and Adipokines in Prostate Cancer. Information relating to the role of myokines such as myostatin and adipokines in prostate cancer is scarce. The crosstalk between skeletal muscles and adipose tissue is of particular interest, as it can shed light on the missing link between physical activity and the progression and regression of prostate cancer (Figure 2).
(Enlarge Image)
Figure 2.
Postulated role of myokines and adipokines in prostate cancer. Adipose tissue secretes proinflammatory adipokines, which in turn leads to a chronic inflammatory environment that promotes prostate cancer. The harmful effects of the proinflammatory adipokines might be counteracted by myokines produced by skeletal muscles. Adapted from Thompson et al.).
Physical activity might favorably or unfavorably change the levels of circulating endogenous factors. It alters the levels of sex hormones (testosterone, estradiol and SHBG) and metabolic hormones and growth factors (insulin and IGF). Physical activity favorably alter testosterone, androgen receptors and SHBG. The androgen receptors and SHBG binds testosterone reducing their ability to negatively influence target tissues. In addition, the SHBG is regulated in part by insulin. Alterations in insulin levels increase SHBG thereby affecting androgen levels. Some of these factors have been associated with prostate cancer risk: insulin and IGFs, and therefore the change in their levels following physical activity may reduce prostate cancer risk. The decrease in these endogenous factors might also decrease mitogenic activity in the prostate.
Several in vitro studies have demonstrated that serum from exercised subjects decreased or inhibited the growth of prostate cancer cells, increased apoptosis of prostate cancer cells, delayed tumor formation and suppressed metastasis. First, physical activity favorably alters the production of serum growth factors that decrease or inhibit growth and increase apoptosis, such as IGFBP-1, epidermal growth factor and IGF-1. Second, physical activity favorably alters proteins that regulate cell cycle progression such as p53, p21 and caspase resulting in growth inhibition and apoptosis, tumor suppression and suppressed metastasis. Third, physical activity reduces production of transcription factors induced in response to abnormal cell physiology that are promoters of malignant progression and metastasis, such as hypoxia-inducible factor 1α and nuclear factor-κB. And finally, physical activity induces humoral effects on the prostate resulting in protection against prostatic lesions. These studies demonstrate that physical activity favorably alters the levels of endogenous factors subsequently regressing prostate cancer. Typically, these studies involve weeks of aerobic physical activity at moderate-to-high intensity.
Inflammatory cells and cytokines contribute to tumor growth, progression and immunosuppression. Inflammation has been shown to be fundamental in prostate cancer. Furthermore, an impaired immune system is susceptible to prostate cancer.
Physical activity has an effect on the inflammatory process. It produces both a short-term inflammatory response and a long-term 'anti-inflammatory' effect that may contribute to the favorable effects of routine physical activity. Studies have shown an association between increased physical activity and reduced inflammation. Physical activity reduces inflammation in conjunction with or independent of changes in body weight and composition. The exact mechanisms by which physical activity reduces inflammation are unknown. Some of the postulated mechanisms include reduction in body fat, reduced accumulation of macrophages in adipose tissue and production of IL-6 and IL-10 by skeletal muscles. The effect of physical activity on tumor suppression is associated with changes in the concentrations of cytokines, such as IL-6 and macrophage chemoattractant protein-1.
To date, there is no evidence demonstrating the role of the immune system in protecting against prostate cancer or elimination of prostate cancer cells. However, overall, the immune system reduces cancer risk by recognition and elimination of tumor cells or through the immune system components. Physical activity boosts the immune system. This is dependent on many physical activity factors, including concentration of endogenous factors, change in body temperature, blood flow, hydration status and body position. Nonetheless the mechanism linking physical activity and immune function are not yet fully elucidated. Available data indicate that physical activity alters the number and function of immune components. It increases the levels of natural killer (NK) cells, NK T cells, macrophages, neutrophils and eosinophils, complements, cytokines, antibodies and T cytotoxic cells. It also alters the NK cytotoxic activity, neutrophil oxidative burst, lymphocyte proliferation or cytolytic activity and lymphocyte activation.
Plausible Biological Mechanisms
Although the precise biological mechanisms are not yet understood, it is postulated that physical activity may reduce the risk of prostate cancer directly or indirectly via inter-related biological pathways (Figure 1). Direct protective effects of physical activity may be mediated by proteins secreted by the skeletal muscles (myokines). Indirect protective effects may be due to the decrease in adiposity, changes in sexual and metabolic hormones, reduction of inflammation and improvement of immune function.
(Enlarge Image)
Figure 1.
Hypothesized mechanisms linking physical activity to prostate cancer risk. Physical activity might decrease risk of prostate cancer via different biological mechanisms (adapted from McTiernan).
The mechanisms linking physical activity to prostate cancer biology have not been fully elucidated. From the papers listed in Table 3 , a number of observations can be made. First, vigorous physical activity upregulates cell cycling and DNA repair pathways and modulates canonical pathways involved in cell signaling and metabolism and Nrf2-mediated oxidative stress response. Second, a number of studies have demonstrated slowed growth and increased apoptosis of LNCaP cells incubated with exercise serum following acute exercise, from those with high levels of physical activity and following a diet and exercise intervention. Mechanistically, there was evidence that these effects were attributable to increased levels of tumor-suppressor proteins such as insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-3, p53, p21 and caspases and decreased levels of tumor-promoting proteins Bcl-2, epidermal growth factor and insulin-like growth factor 1 (IGF-1). There was also evidence of a direct and indirect reduction in inflammation via lower nuclear factor-κB activation in LNCaP cells incubated with postexercise serum. Aerobic exercise training can also decrease IGFPB-3 and increase the IGF-1/IGFBP-3 ratio. In this study, increases in aerobic fitness correlated with favorable levels of leptin and favorable leptin:adiponectin and IGF-1:IGFBP-3 ratios at 3 and 6 months into training. Third, acute to chronic moderate to high intensity aerobic physical activity alters sexual hormones and their receptors. It reduces PSA and androgen receptor expression and increases corticosterone plasma, dihydrotestosterone, testosterone and estrogen receptor α and β expression. The reduction in PSA levels might be through white blood cell modulation. Fourth, physical activity of different intensities reduces inflammation by altering C-reactive protein, interleukin 6 (IL-6), tissue necrosis factor alpha, albumin, fibrinogen, white blood cells and factor VIII activity. These studies suggest that leisure time physical activity may elicit changes to factors which may reduce the risk of prostate cancer by reducing inflammation in young and older adults. Fifth, physical activity induces synergistic effects through oxidative stress modulation. Four weeks of treadmill running in rats reduces prostate tumor proliferation, Bcl-2 expression in tumors, enzymatic antioxidant defense in muscle and thiobarbituric acid reactive substances and 8-oxo-7,8-dihydro-2′-deoxyguanosine levels in tumor. Sixth, physical activity modulates the microenvironment of the tumor by altering the tumor microvascular oxygenation, hypoxia and vascular function. Treadmill training in rats over 5–7 weeks increased tumor microvascular Po2 and reduced tumor hypoxia. Finally, in a series of animal studies, weeks of treadmill running altered inflammatory markers IL-6 and macrophage chemoattractant protein-1, tumor-promoting factors hypoxia-inducible factor 1α and vascular endothelial growth factor and tumor-suppressor proteins caspase-3, humoral and apoptotic factors, which influence the development and progression of prostate cancer.
Where all these studies demonstrate a biological influence of physical activity there is no consensus on the level of activity that is required to change a specific cellular pathway or functional endpoint. The studies have varied frequency, duration and intensity of the physical activity. In addition, each individual participant may respond differently to the physical activity intervention. We propose that a better way of demonstrating the beneficial effects of physical activity is by correlating them to a biological endpoint (that is, a change in a signaling pathway) with a functional outcome (that is, regression of a tumor) rather than the intervention. However, these results suggest that physical activity might reduce the risk of prostate cancer by favorably altering the immune function and signaling pathways relevant to carcinogenesis of the prostate.
Skeletal Muscles and Adipose Tissue
The skeletal muscle has been identified as an active endocrine organ that produces, expresses and releases proteins (myokines). One cause of the production, expression and release of myokines by the skeletal muscle fibers is physical activity, particularly the one involving the contraction of skeletal muscles such as resistance exercise. The effects of physical activity might be transmitted through myokines by affecting body homeostasis. Through the myokine signaling, skeletal muscles can communicate with other organs that could underlie effects of physical activity on systemic health.
The adipose tissue is an endocrine organ that secretes various proteins (adipokines), such as adipsin, leptin and adiponectin. Adiponectin is the only antiangiogenic, antimitogenic and anti-inflammatory adipokine. Although physical activity and muscle mass have a greater effect on insulin kinetics than physical activity and fat mass, physical activity decreases body weight and reduces abdominal fat (adiposity) that alters insulin metabolism. This in turn alters insulin metabolism, which in turn alters blood glucose IGF-1, IGFBP, sex hormones and sex hormone-binding globulin (SHBG). Reducing adiposity alters the levels of adipokines by increasing adiponectin and reducing the proinflammatory adipokines. In addition, physical activity might alter adipose tissue DNA methylation potentially affecting adipocyte metabolism, which might alter adipokine levels, the IGF axis and tumor-suppressor proteins.
Myokines and Adipokines in Prostate Cancer. Information relating to the role of myokines such as myostatin and adipokines in prostate cancer is scarce. The crosstalk between skeletal muscles and adipose tissue is of particular interest, as it can shed light on the missing link between physical activity and the progression and regression of prostate cancer (Figure 2).
(Enlarge Image)
Figure 2.
Postulated role of myokines and adipokines in prostate cancer. Adipose tissue secretes proinflammatory adipokines, which in turn leads to a chronic inflammatory environment that promotes prostate cancer. The harmful effects of the proinflammatory adipokines might be counteracted by myokines produced by skeletal muscles. Adapted from Thompson et al.).
Endogenous Factors
Physical activity might favorably or unfavorably change the levels of circulating endogenous factors. It alters the levels of sex hormones (testosterone, estradiol and SHBG) and metabolic hormones and growth factors (insulin and IGF). Physical activity favorably alter testosterone, androgen receptors and SHBG. The androgen receptors and SHBG binds testosterone reducing their ability to negatively influence target tissues. In addition, the SHBG is regulated in part by insulin. Alterations in insulin levels increase SHBG thereby affecting androgen levels. Some of these factors have been associated with prostate cancer risk: insulin and IGFs, and therefore the change in their levels following physical activity may reduce prostate cancer risk. The decrease in these endogenous factors might also decrease mitogenic activity in the prostate.
Several in vitro studies have demonstrated that serum from exercised subjects decreased or inhibited the growth of prostate cancer cells, increased apoptosis of prostate cancer cells, delayed tumor formation and suppressed metastasis. First, physical activity favorably alters the production of serum growth factors that decrease or inhibit growth and increase apoptosis, such as IGFBP-1, epidermal growth factor and IGF-1. Second, physical activity favorably alters proteins that regulate cell cycle progression such as p53, p21 and caspase resulting in growth inhibition and apoptosis, tumor suppression and suppressed metastasis. Third, physical activity reduces production of transcription factors induced in response to abnormal cell physiology that are promoters of malignant progression and metastasis, such as hypoxia-inducible factor 1α and nuclear factor-κB. And finally, physical activity induces humoral effects on the prostate resulting in protection against prostatic lesions. These studies demonstrate that physical activity favorably alters the levels of endogenous factors subsequently regressing prostate cancer. Typically, these studies involve weeks of aerobic physical activity at moderate-to-high intensity.
Inflammation and Immune Function
Inflammatory cells and cytokines contribute to tumor growth, progression and immunosuppression. Inflammation has been shown to be fundamental in prostate cancer. Furthermore, an impaired immune system is susceptible to prostate cancer.
Physical activity has an effect on the inflammatory process. It produces both a short-term inflammatory response and a long-term 'anti-inflammatory' effect that may contribute to the favorable effects of routine physical activity. Studies have shown an association between increased physical activity and reduced inflammation. Physical activity reduces inflammation in conjunction with or independent of changes in body weight and composition. The exact mechanisms by which physical activity reduces inflammation are unknown. Some of the postulated mechanisms include reduction in body fat, reduced accumulation of macrophages in adipose tissue and production of IL-6 and IL-10 by skeletal muscles. The effect of physical activity on tumor suppression is associated with changes in the concentrations of cytokines, such as IL-6 and macrophage chemoattractant protein-1.
To date, there is no evidence demonstrating the role of the immune system in protecting against prostate cancer or elimination of prostate cancer cells. However, overall, the immune system reduces cancer risk by recognition and elimination of tumor cells or through the immune system components. Physical activity boosts the immune system. This is dependent on many physical activity factors, including concentration of endogenous factors, change in body temperature, blood flow, hydration status and body position. Nonetheless the mechanism linking physical activity and immune function are not yet fully elucidated. Available data indicate that physical activity alters the number and function of immune components. It increases the levels of natural killer (NK) cells, NK T cells, macrophages, neutrophils and eosinophils, complements, cytokines, antibodies and T cytotoxic cells. It also alters the NK cytotoxic activity, neutrophil oxidative burst, lymphocyte proliferation or cytolytic activity and lymphocyte activation.
