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

Antiinflammatory Effects of Physical Activity in Cancer

Given the well-documented benefits of physical activity on tumorigenesis, a quest for the mechanisms responsible for this effect has ensued. However, this has not transpired without challenges. Namely, the mechanisms responsible for the benefits of physical activity on cancer risk are complex and likely to be multifaceted given the very broad pleotropic effects of exercise. Thus, several interrelated factors including adiposity, energy balance, insulin, adipokines, estrogen, and immune function as well as inflammation likely are to be involved, making it difficult to determine the relative contribution of each mechanism.

Inflammation and Cancer

Inflammation plays a significant role in the development and progression of cancer.[13] Data from our laboratory support this notion. For instance, we recently examined the timing and magnitude of inflammation in relation to tumorigenesis in the ApcMin/+ mouse at 8, 12, 16, and 20 wk of age.[23] We reported an increased mRNA expression of MCP-1, IL-1β, IL-6, and TNF-α in the mucosal tissue that is evident at 12 wk of age (Fig. 2) and is consistent with the increase in polyp number that occurs at this time.[23] Further increases in the inflammatory response (i.e., during wk 16 and 20) seemed to be associated with a change in polyp size but not number.[23] Of the inflammatory mediators measured, MCP-1 seemed to be the most responsive.[23] We believed that this warranted further investigation into the role of this chemokine on inflammatory responses and tumorigenesis in this model. Therefore, we performed a follow-up study to examine the role of MCP-1 on inflammation and tumorigenesis by crossing the ApcMin/+ mouse with an MCP-1–knockout mouse.[24] MCP-1 deficiency decreased overall polyp number and abundance of large polyps, which was consistent with a reduced expression of inflammatory cytokines in the intestinal tissue and polyps as well as circulating levels of IL-6.[24]

Figure 2.

Messenger RNA gene expression of inflammatory mediators in the Apc Min/+ mouse at 8, 12, 16, and 20 wk of age. Differences in mRNA gene expression of (A) IL-6, (B) TNF-α, and (C) MCP-1 were observed in the intestines across time (n = 6–12 per group). P < 0.05 * greater than 8 wk, # greater than 12 wk, ! greater than 16 wk, and @ greater than 20 wk. Correlations were performed between large polyp number and mRNA expression of (D) IL-6, (E) TNF-α, and (F) MCP-1. [Adapted from (23). Copyright © 2012 Elsevier. Used with permission.] All inflammatory mediators showed a positive relationship with large polyps (P < 0.001).

We performed a similar study to examine the role of MCP-1 on breast cancer in the C3(1)SV40Tag mouse model of mammary tumorigenesis using a pharmacological approach.[35] To inhibit MCP-1, we used bindarit (2-((1-benzyl-indazol-3-yl) methoxy)-2-methyl propionic acid), a well-characterized small synthetic indazolic derivative best known for its transcriptional inhibition of the monocyte chemoattractant subfamily of CC chemokines including MCP-1/CCL2.[27] Bindarit treatment reduced tumor number but did not affect tumor size, tumor weight, or tumor latency in C3(1)/SV40Tag mice.[35] Within the tumor, mRNA expression of bindarit's primary targets, MCP-1 and IL-12/p35, was significantly decreased, and this was consistent with trends for reduced expression of TNF-α, IL-6, and IL-10.[35]

Given the well-established role of inflammation in cancer, it has become a target for cancer prevention and therapy. As such, we recently have seen an increase in the investigation of antiinflammatory chemoprevention strategies in cancer including physical activity.

Interleukin-6

IL-6 is a cytokine that has been associated with poor prognosis in various cancers including that of the colon and breast. For example, Baltgalvis et al.[4] used IL-6–knockout mice and plasma-based IL-6 overexpression to examine the role of IL-6 in tumorigenesis and reported that ApcMin/+/IL-6−/- mice had a decrease in overall polyp number, whereas overexpression of IL-6 increased polyp burden.[4] Similarly, we have documented an increase in circulating levels of IL-6 in a mouse model of breast cancer.[28]

Several studies have addressed the effects of physical activity on IL-6 in colon cancer models. A study by Mehl et al. reported a decrease in circulating IL-6 in male ApcMin/+ mice after treadmill running that was associated with a decreased polyp number. Interestingly, IL-6 also was decreased in male mice exposed to wheel-running activity as well as female mice that underwent both treadmill exercise and wheel-running activity, but there was no benefit on tumorigenesis in these treatment groups implicating that exercise can decrease IL-6 independent of any effects on tumorigenesis. Given the age-induced increase in intestinal inflammation and associated elevated risk for colon cancer, a recent study examined the effects of voluntary wheel running on IL-6 expression in intestinal lymphocytes in older adult mice.[31] Although other inflammatory mediators were reduced with voluntary exercise, there was no reported reduction in IL-6.[31] To our knowledge, there are no studies that have examined IL-6 levels after an exercise intervention in colon cancer patients or survivors.

Although limited, there have been a few investigations that have examined the relationship between exercise, IL-6, and breast cancer. For example, we examined the effects of daily treadmill running on circulating IL-6 in the C3(1)SV40Tag mouse model of breast cancer and found a significant decrease in plasma IL-6 after 20 wk of training (Fig. 3A), which was consistent with a reduction in tumor number and volume.[28] Similarly, it has been demonstrated that voluntary wheel-running activity is effective at reducing plasma IL-6 in a chemically induced rat model of breast cancer.[37,38] Although the limited animal literature shows positive findings, the available epidemiological evidence is less convincing. For example, the Yale exercise and survivorship study investigated the effects of 6 months of aerobic exercise on IL-6 levels in postmenopausal breast cancer survivors.[19] Although there were no significant effects of the exercise intervention on circulating IL-6 levels, interestingly, secondary analyses revealed a significant reduction in IL-6 among exercisers who reached 80% of the intervention goal compared with those who did not.[19]

Figure 3.

Exercise decreases plasmaMCP-1 and IL-6 in the C3(1)SV40Tag mouse model of breast cancer. Mice were run on a treadmill from 4 to 24 wk of age. Plasma concentrations of IL-6 (A) and MCP-1 (B) were determined at 24 wk of age. [Adapted (28). Copyright * 2011 Elsevier. Used with permission.] Wild-type mice were used as a control. Values are means ± SEM. * Significantly different from wild type P < 0.05.

Tumor Necrosis Factor-α

Another inflammatory cytokine with protumorigenic properties is TNF-α, although its role remains somewhat controversial. Based on the available literature, it seems that TNF-α is more detrimental during the early stages of carcinogenesis and at lower sustained doses, whereas antitumor effects have been reported at higher doses. Nonetheless, the majority of evidence supports a negative effect of TNF-α in tumorigenesis given its role in promoting inflammatory processes.

Like IL-6, some, but not all, studies have reported a reduction in TNF-α with physical activity. In a mouse model of chemically induced colon cancer, it was reported that 6 wk of regular treadmill exercise results in a decrease in TNF-α in the colon and plasma, and this was consistent with a suppression of aberrant crypt foci.[1] Similarly, it was found that voluntary wheel running reduces TNF-α expression in intestinal lymphocytes of older adult mice, which may have implications for colon cancer.[31] Although the sample size was relatively small, a 12-wk home-based exercise program resulted in a significant decrease in circulating TNF-α levels in patients with stage II to III colorectal cancer.[21]

In a chemically induced rat model of breast cancer, it was reported that voluntary wheel running reduced tumor burden, which was associated with a decrease in circulating levels of TNF-α among other cancer-related biomarkers.[38] In a recent pilot study, stage I, II, or IIIA breast cancer survivors were randomized to either a 3-month physical activity intervention or control treatment. After the exercise intervention, there was a small but nonsignificant decrease in TNF-α.[32] In the Yale exercise and survivorship study, postmenopausal breast cancer survivors underwent a 6-month aerobic exercise regimen, but there were no reported changes in TNF-α levels.[19] Similarly, in the Alberta Physical Activity and Breast Cancer Prevention Trial, a randomized control trial in healthy postmenopausal women to examine the effects of moderate to vigorous aerobic exercise on circulating inflammatory markers, there was no statistically significant decrease in TNF-α after 12 months on the exercise intervention.[11] Similar to IL-6, the animal data support an inverse relationship between physical activity and TNF-α, whereas the human literature remains largely inconsistent.

Monocyte Chemoattractant Protein 1

Although the evidence for a role of MCP-1 in cancer is considerable, there currently is very limited work on the relationship between exercise and MCP-1 in cancer models. In fact, to our knowledge, any investigation of an effect of exercise on MCP-1, at least for colon cancer and breast cancer, is limited to work performed in our laboratory. We examined the effects of exercise on macrophage chemoattractants, including MCP-1, in the ApcMin/+ mouse model of intestinal tumorigenesis. Treadmill exercise for 12 wk resulted in a decrease in the number of large polyps, but there was no significant decrease in MCP-1 or any of the other chemoattractants measured.[25] On the contrary, we recently examined the effects of daily treadmill running on circulating MCP-1 levels in the C3(1)SV40Tag mouse model of breast cancer and found a significant decrease in plasma MCP-1 after 20 wk of training (Fig. 3B), which was linked to a reduction in tumor number and volume.[28] Additional studies in rodents as well as clinical investigations are necessary to establish a potential relationship between physical activity and MCP-1 in cancer.

Direct Effects and/or Innocent Bystander?

Although the available studies are limited and not all investigations have reported a decrease in inflammatory mediators with physical activity, there certainly is evidence to support the hypothesis that the benefits of physical activity on tumorigenesis are associated with a decrease in inflammatory markers. What is not clear, however, is whether these benefits are a result of a direct effect on inflammatory pathways that are essential for tumorigenesis or purely just a bystander effect of the recognized relationship between physical activity and cancer?

The evidence from controlled experimental studies in animals to date is limited to data that simply support an association between physical activity, reduced tumor burden, and decreased inflammation. Mechanistic studies to determine whether physical activity is influencing tumorigenesis via a direct effect on certain inflammatory mediators are just not available. The human literature is even scarcer with the majority of the few existing studies limited to measurement of inflammatory mediators in cancer survivors after physical activity interventions. There is, however, a literature base to support an antiinflammatory effect of physical activity in nondiseased models. Thus, it is certainly possible that physical activity directly can influence inflammatory pathways. However, given the very broad pleiotropic effects of physical activity, it is likely that physical activity is affecting several interrelated pathways that are known to influence cancer development and progression (Fig. 4).

Figure 4.

Mechanisms for a benefit of exercise on tumorigenesis. Exercise may have a direct effect on inflammatory pathways that are critical for cancer growth or may merely be a bystander effect of alterations in other pathways that are known to affect cancer progression and development.

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