158 Exercise, Breast Cancer, Macrophages

Exercise, Physical Activity and Breast Cancer:

The Role of Tumor-Associated Macrophages
Jorming Goh1, 2, Elizabeth A. Kirk1, Shu Xian Lee2, Warren C. Ladiges2, *
1
2

Interdisciplinary Program in Nutritional Sciences, University of Washington,

WA Seattle, USA.
Department of Comparative Medicine, University of Washington, WA Seattle,
USA.

ABSTRACT
Regular exercise and physical activity provide many health benefits and are
encouraged by medical professionals for the primary prevention of, and adjuvant
treatment of breast cancer. Current consensus in the discipline of exercise oncology is that both regular physical activity and exercise training exert some protective effect against breast cancer risk, and may reduce morbidity in some advanced
cases. While there is growing interest in the role of exercise and physical activity
in breast cancer prevention, it is currently unclear how exercise may modulate
tumor behavior. The tumor microenvironment is populated by stromal cells such
as fibroblasts and adipocytes, as well as macrophages. Termed tumor-associated
macrophages (TAMs), these immune cells are highly plastic and respond to different signals from the cancer microenvironment, causing them to either display
tumor-promoting or tumor-suppressing phenotypes. Because of such plasticity,
there has been considerable interest by immunologists to develop immunotherapies based on skewing the behavior of TAMs to become cancer-suppressive. Previous studies have indirectly shown the ability of exercise training to induce an
anti-tumor effect of macrophages, although the studies did not address this in the
tumor microenvironment. Nevertheless, this opens up the possibility that regular
exercise training may exert a protective innate immune effect against breast cancer, potentially by inducing a cancer-suppressing phenotype of TAMs. This
review will describe potential mechanisms through which exercise may modulate
the behavior of TAMs.
Key words: Exercise, physical activity, breast cancer, microenvironment, tumorassociated macrophages.

Address for correspondence:

Warren C. Ladiges DVM, MS. Professor, Department of Comparative Medicine,
University of Washington. Email: wladiges@uw.edu

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Exercise, Breast Cancer, Macrophages 159

INTRODUCTION
Breast cancer is the primary type of cancer afflicting women in the United States
of America (51). The American Cancer Society estimated up to 226,000 American women to be newly diagnosed with breast cancer in 2012 (51). Importantly,
this disease is the second leading cause of deaths among different cancer types in
American women, with an expected 40,000 deaths in 2012 (51). Breast cancer is a
disease of the mammary gland. The normal mammary gland is comprised of
Figure
1.
branching
mammary milk ducts, containing ductal epithelial cells, that terminate
in the lobule with luminal epithelial cells forming an inner lining in the lobular
lumen (Figure 1). Surrounding these cells are the extracellular matrix and stromal
cells (fibroblasts, endothelial
cells, leukocytes, adipocytes)
of the microenvironment.
Similar to other types of cancer, the progression of breast
cancer follows a sequential
series of events: initiation,
promotion and progression
(35). Initiation occurs when
DNA in mammary epithelial
cells encounters some form of
deleterious interaction with a
carcinogen. A DNA adduct is
formed and results in the
erroneous
insertion of the
Figure 1. The normal mammary gland is comprised of a
branching duct, containing ductal epithelial cells, that complementary nucleotide
leads to the lobule. In the lumen of the lobule are the during DNA transcription. At
luminal epithelial cells. Different stromal cells reside in this stage, without a supportthe mammary gland microenvironment, such as fibrob- ive microenvironment, the
lasts (yellow), macrophages (green), endothelial cells
initiated epithelial cells
(red) and adipocytes (white). During tumorigenesis, the
interaction of these stromal cells with the epithelial cells remain latent and will not
develop into tumors. In the
influences the progression of the disease.
promotion stage, initiated
epithelial cells are exposed to
promoters that increase their proliferation. The proliferation of these epithelial
cells is not permanent, as removal of the promoters would reverse this process. In
the progression state, initiated cells become tumors when a second genetic event
allows the initiated cells to become permanently altered. Some of these cells
acquire a selective growth advantage and become malignant. Malignant cells proliferate uncontrollably and in advanced stages, spread to distant organs (metastasis), resulting in death. In recent years, the role of the tumor microenvironment in
cancer biology has been better understood. It is apparent that tumor cells communicate with stromal cells in the microenvironment in a complicated, bi-directional
crosstalk. The outcome of this crosstalk then influences the response of the tumor
cells.
The terms tumor and cancer have been used interchangeably, but it is important to differentiate the two. A tumor is an amalgamation of cell mass, and can be
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160 Exercise, Breast Cancer, Macrophages

benign or malignant. A benign tumor grows slowly, seldom divides and has morphological characteristics similar to the tissue it arose from (35). In contrast, cancer is a malignant tumor that has lost the regulatory control mechanisms for cell
proliferation and division (35). In this review, the term tumor will be used when
describing a cancer phenotype and the tumor microenvironment. This is pertinent
when describing i) the primary tumor, localized to the site of origin, and ii) the
secondary tumor, when the primary tumor has breached the basement membrane
and seeded individual tumor cells into the blood circulation that metastasize to
distant locations. Metastasis is the final stage in the development of breast cancer
and ends with the death of the host.
The risk factors of breast cancer have been identified and are attributed to i)
genetic heritability; carriers of mutated BRCA1 and BRCA2 gene have increased
risk of breast cancer (46) and ii) environmental influences, such as diet and physical activity (53). Thus, the combination of both susceptible genes and poor
lifestyle behavior can contribute to increased breast cancer risk, suggesting that
lifestyle behavior is one modifiable risk factor for cancer. Physical activity is one
such modifiable risk factor. It is defined as skeletal muscle contraction that results
in increased energy expenditure above basal levels (4). It includes activity that is
related to home maintenance (e.g. gardening), occupation (e.g. construction),
commuting (e.g. biking to work) or recreation (e.g. sports, dance etc) (4). Exercise is a subset of physical activity, where it is planned, repetitive and structured,
with the goal of improving or maintaining physical fitness (4). Exercise can be
further categorized as acute or chronic, where the former typically refers to
one bout of activity, and the latter refers to regular, periodic bouts of activity.
Throughout this text, the distinction between physical activity and exercise
are made when referring to the pertinent studies. This distinction is important for
several reasons. First, in epidemiological studies, physical activity is an independent variable that is observed but not manipulated, whereas exercise is an independent variable that is manipulated in randomized controlled trials or other
forms of interventional studies. This suggests that the degree of experimental control is different, with the "dose" (frequency, intensity, time, type) of physical
activity more variable amongst subjects in physical activity studies, compared
with exercise studies. Second, outcomes from observational studies depict correlations between physical activity and disease outcome. Experimentally, it is difficult to elucidate the mechanistic effects of physical activity on cancer outcomes
because physical activity usually spans a broad definition and the amount of physical activity performed is neither uniform nor controlled, leading to inter-subject
variation. Finally, manipulation of the independent variable (exercise) is necessary in order to determine cause and effect.
Exercise training or physical activity could be protective against cancer by
regulating the behavior of macrophages in the tumor microenvironment. Research
has shown that exercise exerts modulatory effects on macrophage metabolism,
phagocytosis, chemotaxis, and anti-tumor activity (66). Therefore, it is relevant to
understand how their beneficial effects against breast cancer can be harnessed
with exercise training or regular physical activity. A paradox in breast cancer and
tumor-associated macrophages (TAMs) exists, whereby the presence of the TAMs
in the breast microenvironment is usually correlated with poor prognosis. Yet,
experimental models have often shown that macrophages are capable of destroyEIR 18 2012

Exercise, Breast Cancer, Macrophages 161

ing tumors (22). It may be possible that the paradox depends on the phenotype of
the macrophages present, which will be the focus of this review. It is acknowledged that other cellular mechanisms such as anti-oxidative effects and metabolic
alteration on tumor cells may contribute to the exercise-induced effects on carcinogenesis and metastasis, but they are beyond the scope of this review.
Physical Activity Attenuates Breast Cancer Risk and Improves Survival in
Human Epidemiology Studies
In order to define the dose of physical activity in epidemiological studies, scientists typically report the weekly caloric expenditure of their subjects. Caloric
expenditure in this case, is measured in terms of metabolic equivalents (MET)s,
which is the oxygen cost of a physical activity expressed as a ratio to oxygen cost
at rest. These MET values are used widely and obtained from the compendium of
physical activity (1). It has been well described that regular physical activity is
associated with decreased incidence of some cancers. A five-year prospective follow up of a cohort of post-menopausal women showed, after controlling for confounding factors, that women with the highest baseline levels of physical activity
had a 29% lower incidence of breast cancer compared to women who were least
physically active (38). The most physically active women expended 42 metabolic
equivalents (MET) hours per week, whereas the most sedentary women expended
between 1-7 MET hours per week (38). In a systematic literature review (15), a
total of 87 cohort studies and case-control studies specific to different types of
physical activity (recreational, occupational, transport, household) and breast cancer were retrieved and studied. The overall finding was a 25% risk reduction for
cancer risk amongst women in the most physically active group, compared with
the least physically active women. In addition, the authors reported a doseresponse relationship, where participation in vigorous intensity physical activity
was associated with a greater decrease in breast cancer risk, compared with moderate intensity physical activity (mean decrease of 26% versus 22%). Agreeing
with these findings, another study showed that American women between the
ages of 35 and 64 years, who participated in recreational physical activity
throughout their lifetime, had a 35% reduced risk of developing invasive breast
carcinoma, compared with women that were sedentary (39).
In July 2010, an expert panel from the American College of Sports Medicine reviewed current studies of exercise training and cancer survivorship and
released a roundtable consensus statement, concluding that exercise training is
safe during and after cancer treatments and results in improvements in physical
functioning, quality of life, and cancer-related fatigue (49). The panel also stated
that exercise training before and after breast cancer diagnosis is associated with a
decrease in the risk of recurrence and/ or death from breast cancer. In this regard,
Schmidt (48) reported that four of six cohort studies have shown a protective
effect of pre-diagnosis physical activity on breast cancer survivorship, whereas
two studies did not. In another prospective cohort study that recruited women
diagnosed with either in situ or regional cancer (27), participation in physical
activity after breast cancer diagnosis had a stronger protective effect compared
with pre-diagnostic physical activity. In this study, compared with inactive
women, physically active women who expended a minimum of 9 METs per week
prior to diagnosis, had a hazard ratio for total deaths of 0.69 (95% CI, 0.45 to
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162 Exercise, Breast Cancer, Macrophages

1.06, P=0.045), compared with a hazard ratio for total deaths of 0.33 (95%CI,
0.15 to 0.73, P=0.046), for women that were physically active 2 years after diagnosis. These results have been corroborated by similar findings by other studies
(24, 25). In the Holick study (24), women between the ages of 20 and 79 years
and diagnosed with invasive breast cancer were recruited into a prospective study
and followed for an average of 6 years. The authors reported that compared with
women that were sedentary, women expending 21 or more MET hours per week
had a lower risk of breast cancer mortality (hazard ratio, 0.51; 95% CI: 0.29-0.89;
P for trend =0.05). Finally, in the Nurses Health Study (25), women aged 30-55
years and diagnosed with breast cancer (stages I-III) were enrolled in a prospective observational study. During the follow up period, it was observed that postmenopausal women that participated in moderate physical activity (greater than 9
METS hours per week) had a reduced risk of breast cancer mortality (relative
risk, 0.73; 95% CI: 0.54, 0.98), compared with women that expended less than 9
METS hours per week. In addition, the hormonal levels of breast cancer also
appeared to be influenced by physical activity. Moderate physical activity was
shown to exert a more protective effect in women that were physically active and
had estrogen receptor (ER)- positive and progesterone receptor (PR)-positive
breast cancers than women with ER-negative and PR-negative breast cancers
(odds ratio 0.50; 95% CI: 0.34-0.74 versus odds ratio 0.91; 95% CI: 0.43-1.96).
It is concluded that epidemiological studies generally support the use of
physical activity and exercise training after diagnosis of breast cancer, suggesting
that this type of life style change may slow the progression of breast cancer and
perhaps also reduce the risk of recurrence and hence improve survivorship. However, unresolved questions remain regarding the effect on immunity. The only
clinical studies that investigated the role of the immune system in cancer and
exercise intervention in human subjects, have thus far have involved NK cells (11)
and lymphocytes (26) in the blood circulation. We speculate that TAMs represent
an under-studied cell population in the tumor microenvironment, particularly as it
relates to exercise oncology. It is unknown whether exercise training or physical
activity modulates the immune response in the tumor microenvironment, and if
so, what mechanisms are involved. Elucidating these mechanisms can identify
how macrophages and their secreted factors can play a role in reduced metastasis
and explain the improved survivorship for physically active women with breast
cancer.
Macrophages in the Tumor Microenvironment Modulate Tumor Behavior
The seed and soil hypothesis suggests that for tumor cells (seeds) to propagate and advance to malignancy, the tumor microenvironment (soil) has to be
permissive and supportive of their growth (38). In other words, stromal cells
secrete factors and cross-talk with tumor cells to display the phenotypic hallmarks
of cancer, such as self-sufficiency in growth and increased invasiveness and
metastatic potential. Macrophages in the tumor microenvironment, referred to as
TAMs, are stromal cells that can influence tumor behavior. Macrophages are
recruited into the tumor microenvironment where they differentiate to become
TAMs. In general, the presence of TAMs is associated with poor prognosis in cancer survivors (42). This clinical outcome is likely attributed to TAMs role in supporting tumor progression (increased tumor proliferation, vascularization, tissue
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Exercise, Breast Cancer, Macrophages 163

invasion and metastasis). In paraffin embedded, archived samples of human mammary carcinoma, a higher count of macrophages in random high powered fields,
shown by positive cluster of differentiation (CD) immunostaining was correlated
with less than 5 years of survival, compared with samples that stained for a lower
count of macrophages (19).
The role of macrophages in malignancy was well characterized in a murine
model of cancer, where knock out of the gene encoding the macrophage growth
factor, colony-stimulating factor (CSF)-1, resulted in the growth of benign mammary cancers with a reduction in pulmonary metastasis (31). In breast cancer,
CSF-1 expressed by epithelial carcinomas promotes the recruitment of
macrophages to the tumor microenvironment (42). Once these macrophages
arrive, they produce epithelial growth factor (EGF) that in turn, enhances the
migration and invasion capabilities of mammary carcinomas in a CSF-1-dependent manner (20). Furthermore, primary tumors induce the upregulation of inflammatory chemokines, S100A8 and S100A9, which recruit macrophage antigen
(MAC)-1 myeloid cells in the pre-metastatic tumor microenvironment (23). In
this study, administration of S100A8 and S100A9 antibodies prevented the development of pseudopodia in the primary tumor cells, as well as the migration of primary tumor cells and MAC-1 myeloid cells to the pre-metastatic sites, suggesting
that certain sub-populations of macrophages are responsible for promoting tumor
metastasis.
Even though increased populations of TAMs in the tumor microenvironment have been associated with a poor clinical prognosis, it must be noted that
TAMs are phenotypically diverse, reflecting their plasticity within different tissue
microenvironments. Two different sub-populations of activated macrophages
have been described, namely, classically activated, or M1 macrophages, or
alternatively activated, or M2 macrophages (47). This nomenclature is a simplistic view of the complicated functions and behavior of macrophages, but is
used to functionally distinguish the cytokine signals that induce their differential
polarization. The main phenotypic characteristics of M1- and M2 tumor-associated macrophages are listed in Figure 2.
M1 macrophages are activated in response to bacterial lipopolysaccaride
(LPS) and interferon (IFN)-. In turn, they secrete tumor necrosis factor (TNF)-,
interleukin (IL)-12, reactive oxygen species (ROS) and reactive nitrogen species,
as evidenced by the up-regulation of inducible nitric oxide synthase (iNOS) (47).
Secretory products such as TNF- and ROS can destroy cancers (47) while iNOS
has been demonstrated to enhance the anti-tumor effects of doxorubicin (8). As
well, IL-12, a heterodimeric cytokine is secreted by macrophages to activate natural killer (NK) cells (21) and also activate T-helper 1 (Th1) cells to elicit antitumor immune responses (10). Nuclear Factor-kappa B (NF-B) activation by the
binding of the p50 and p65 subunits is also another characteristic of M1
macrophage activation (50). Although tumor cells down-regulate major histocompatibility complex (MHC)-I molecules to escape immune detection, dying primary tumor cells express extracellular damage-associated molecular patterns
(DAMPs), such as high mobility group box protein (HMGB)-1 and heat shock
proteins (HSPs) (16). These are detectable by macrophages via toll-like receptors
(TLRs) (16). Purified HSP70 from mice with Daltons Lymphoma was able to
reverse the immunosuppressive macrophage phenotype induced by the tumor,
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164 Exercise, Breast Cancer, Macrophages

Figure 2: Characteristics of M1 and M2 macrophages. M1 macrophages produce high

amounts of TNF-alpha, IL-1, IL-12 and low amounts of IL-10 and TGF-beta. Conversely M2
macrophages produce high amounts of IL-10 and TGF-beta, and low amounts of TNFalpha, IL-1 and IL-12. M1 macrophages are cytotoxic and pro-inflammatory, whereas M2
macrophages support tumor growth and are associated with wound repair and tissue
remodeling.

suggesting that HSP70 can change the polarization status of M2 macrophages to

that of M1 (30).
There is practical rationale for investigating the effects of M1 macrophages
in breast cancer because they play a role in tumor regression. These anti-tumor
abilities of macrophages were reported in a study conducted by Hicks and colleagues (22). The authors generated a line of mice that displayed resistance
against experimental tumor induction. These mice were named spontaneous
regression/ complete resistance (SR/ CR) mice because they were able to either
completely eradicate injected cancers, or to prevent the cancers from growing.
Intriguingly, when the macrophages from these mice were injected into wild-type
mice, the latter also developed resistance to the experimental cancer. This study
suggests that macrophages are capable of recognizing and destroying certain cancers and hence useful for clinical immunotherapy. Although the polarization state
of the macrophages was not investigated in that study, it is probable that they may
share characteristics of M1 macrophages.
Unlike M1 macrophages, M2 macrophages are activated by the cytokines
IL-4, IL-10, and IL-13 as well as glucocorticoids, while secreting factors and
cytokines such as vascular endothelial growth factor A (VEGFA) (pro-angiogenic), IL-10 (inhibits dendritic cell maturation and promotes Th2 response) and
matrix metalloproteinases (MMPs-2, -7, -9, -12) (47). Additionally, the balance of
L-arginine metabolism in macrophages is also indicative of the direction of polarization to either M1 or M2 macrophages in the tumor microenvironment. M1
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Exercise, Breast Cancer, Macrophages 165

macrophages catalyze L-arginine to synthesize nitric oxide and L-citrulline,
whereas M2 macrophages catalyze the hydrolysis of L-arginine to form Lornithine and urea (50). A depletion of L-arginine in the tumor microenvironment
can then inhibit T lymphocyte function and induce immunotolerance (47).
A certain sub-population of immature myeloid cells, termed myeloid-derived
suppressor cells (MDSCs), further influences macrophage polarization in the
tumor microenvironment (37). The presence of MDSCs in the tumor microenvironment has been reported in many cancers, including breast tumor and evidence
suggests that MDSCs suppress immunosurveillance, and promote cancer progression and metastasis (54). MDSCs express the surface receptors CD11b and granulocyte differentiation antigen (Gr)-1 (57), originate from the bone marrow and are
found in the tumor microenvironment. This is where they cross-talk with
macrophages via cell-to-cell contact to induce the M2 phenotype, with an increase
in IL-10 production that cause a corresponding decrease in IL-12 production by
macrophages. The reduced macrophage production of IL-12 is particularly significant, since it dampens natural killer (NK) cell activity and also polarizes M1
macrophages toward the M2 phenotype (52). As well, increased MDSC production
of IL-10 skews CD4+ and CD8+ T cells toward a cancer-promoting program and
also inhibits dendritic cell (DC) maturation (52). Thus, macrophage polarization in
the tumor microenvironment is influenced by complex cross-talk with MDSCs.
The macrophage phenotype is typically M2 in the tumor microenvironment.
However, recent research also suggests that the phenotype of TAMs might not
simply be M2, but a more progressive transition from M1 to M2, as the tumor
becomes malignant and induces a different array of molecular signaling (47).
Thus, it is conceivable that M1 macrophages are first polarized within an initiated
tumor. With progressive growth and acquisition of malignancy, M1 macrophages
might then be polarized to differentiate towards M2 macrophages, which then
become pro-tumor and become the tumor-educated macrophages that Pollard
hypothesized (43).
Physical Activity or Exercise Modulates Macrophage Anti-tumor Activity
Exercise or physical activity has a profound effect on macrophage physiology,
including phagocytosis, chemotaxis, metabolism and anti-tumor activity (66). In
murine models of acute exercise, peritoneal macrophage phagocytosis (12) was
increased in vitro, relative to sedentary conditions. In young, healthy humans subjected to strenuous interval training (running and cycling), an exercise-induced
decrease in monocyte chemotactic protein (MCP)-1 induced monocyte chemotaxis was observed (7). This contrasts with the increase in macrophage recruitment in the murine models described above. However, it must be noted that the
murine studies utilized acute bouts of exercise, whereas the human study utilized
a three-week exercise training protocol. It would be interesting to compare the
effects of macrophage recruitment in murine models after exercise training, compared with acute exercise. The physiological implication of this study suggests
that exercise training may be anti-inflammatory, in that there may be a decrease
in monocytes being recruited into a pre-malignant tumor microenvironment. Perhaps one anti-tumor mechanism induced by exercise could involve a reduction in
macrophage presence in the tumor microenvironment. What is clearly needed is
to determine whether polarized phenotypes are different with exercise training.
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166 Exercise, Breast Cancer, Macrophages

Woods and colleagues reported other macrophage functions that were modulated with acute exercise (61, 62, 63, 64, 65). In one of their studies, male
C3H/HeN mice pre-assigned to either three days of moderate-intensity or exhaustive treadmill running were injected subcutaneously with SCA-1 adenocarcinomas. Subsequently, the mice were exercised for an additional 14 days (64). Moderate-intensity exercise resulted in greater numbers of highly phagocytic cancerinfiltrating macrophages compared with either controls or exhaustive exercise.
Tumor incidence, defined as the onset of palpable cancers, was delayed in the
control group on the 7th day after implant compared with either of the exercise
groups. However, final tumor weights were not different between groups. This
suggests that short-term exercise training in C3H/HeN mice slowed the early
onset of tumor growth, but was ineffective in reducing the final tumor burden.
This lack of a robust effect may be due to the dose of the exercise given, which
was a few days of treadmill running. A long-term exercise protocol greater than
two weeks may be needed to stimulate a stronger anti-tumor effect.
To address the mechanistic effects of acute exercise on macrophage activation (64) and inflammatory macrophage response (65) against cancers, male
C3H/HeN mice were injected intraperitoneally with thioglycollate (64, 65) or
propionibacterium acnes (64) to induce peritoneal inflammation and macrophage
influx. The mice were then subjected to acute moderate-intensity treadmill running or exhaustive treadmill running for three consecutive days post-injection
before they were sacrificed. The significant finding from both studies was that
compared with controls, moderate-intensity and exhaustive treadmill running
resulted in enhanced macrophage cytotoxicity against spinocerebellar ataxia
(SCA)-1 cancer cells in vitro, as measured by the reduced [3H] Thymidine incorporation by the cancer cells, a marker of cell proliferation. Acute exercise had neither effect on the percentages of macrophages in peritoneal cells nor the number
of macrophages that adhered to culture dishes, suggesting that quantitative
changes in macrophage numbers may not be responsible for the phenotypes
observed with acute exercise. These two studies also suggest that peritoneal
macrophage anti-cancer cytotoxicity may be modulated with acute exercise in
vitro, but do not give any indication of TAM function nor the types of
macrophages (M1 or M2) that are recruited into the cancer microenvironment. As
discussed earlier, TAMs either inhibit or stimulate cancer growth and metastasis,
depending on their polarized phenotype. Zielinksi and colleagues (67) reported
that in female BALB/c mice that ran on treadmills for two weeks after implantation of allogeneic lymphoid cancers, macrophage infiltration into the cancers
were significantly lower than control sedentary mice. Whether such an effect is
seen in other cancer models, strains of mice, or the phenotype of macrophages
that were reduced is unclear, but is an important issue to address.
Not all acute or short-term exercise-induced changes in macrophage functions are necessarily beneficial. Antigen presentation by macrophages may be
down-regulated. To illustrate this, male BALB/c mice were injected with thioglycollate and then subjected to moderate-intensity or exhaustive treadmill running
for four consecutive days (5). Upon sacrifice, peritoneal exudate cells were harvested, washed to remove non-adherent cells, and incubated with T-hybridoma
cells and chicken ovalbumin. Chicken ovalbumin was used as an antigen for
macrophage antigen presentation to the T-hybridoma cells, and the resultant proEIR 18 2012

Exercise, Breast Cancer, Macrophages 167

duction of IL-2 by the hybridoma cells was a direct measure of macrophage antigen presentation. Exercised mice showed decreased IL-2 concentrations, as measured by an enzyme linked immunosorbent assay (ELISA) kit at different concentrations of ovalbumin, thus suggesting a suppression of macrophage antigen presentation, allowing the cancer to escape immune detection and cytolysis. An exercise training study that was of longer duration was also conducted. It involved
young (6 months) and old (22 months) BALB/c male mice made to run on treadmills for four months (32), the investigators observed that compared with sedentary controls, exercise training increased macrophage cytolysis of P815 cancer cell
lines, although the effect was stronger in the young mice. In addition, macrophage
production of nitric oxide was also increased in exercised mice, with an increased
gene expression of iNOS in the young exercised mice, but not old exercised mice,
suggesting that the cytotoxic effects may not be mediated via iNOS.
The conclusion drawn from these studies is that exercise training in mice
generally enhances the anti-tumor effect of macrophages in vitro. Discrepancies
in the findings from the various studies may be due to differences in exercise
duration and/or intensity, length of exercise training, diet protocol, dosage or timing of tumor cells or carcinogens injected and strain of rodents studied. In some
cases, discrepant results may stem from the fact that some unidentified subsets of
dendritic cells, which play a bigger role in antigen presentation than
macrophages, may influence the immune response in cooperation with, or independent of macrophages after exercise.
Can Physical Activity or Exercise Training Shift Macrophage Polarization?
Exercise training in mice appears to shift macrophage polarization, at least as
extrapolated indirectly from the cytokine milieu of three animal studies. In the
first study (58), 10 days of treadmill running in male BALB/c mice transplanted
intraperitoneally with Daltons lymphoma resulted in reduced vascularization
around the peritoneal region, compared with sedentary control mice. This observation was accompanied by the reduction of VEGF expression, decrease in the
number of erythrocytes in peritoneal fluid, and increase in oxygen concentration
in Daltons lymphoma cell-free ascitic fluid. Finally, the authors reported that the
peritoneal fluid from exercised mice had a higher concentration of Th1 cytokines,
compared with Th2 cytokines, such that there was an increase in IFN- and a
decrease in IL-4 and IL-10. In the second study (29), three weeks of treadmill
running increased LPS-stimulated NO, IFN- and TNF- production in peritoneal
macrophages of male BALB/c mice, compared with control, sedentary mice. On
the other hand, the production of IL-10, a cytokine that is commonly associated
with M2 macrophages, was lower in trained mice versus control mice. Finally, in
the third study (32), exercise training increased macrophage production of nitric
oxide, concomitant with increased iNOS gene expression. This effect was however, attenuated in old mice.
The first study suggests that exercise training in cancer-bearing BALB/c
male mice may shift the cytokine balance from a Th2 to a Th1 phenotype, at least
in the cancer microenvironment. The second study indirectly corroborates the
first, and suggests that biomarkers of M1 macrophages appeared to be increased
in peritoneal macrophages of healthy, exercise-trained BALB/c male mice.
Although the first study was conducted using Daltons lymphoma, there is a posEIR 18 2012

168 Exercise, Breast Cancer, Macrophages

sibility that exercise training or physical activity may result in a similar outcome
in mammary carcinoma. The exercise-induced phenotypes in BALB/c mice from
both studies suggest a shift in macrophage polarization, although whether these
phenotypes extend to mice of other strains is unclear. For example, bronchoalveolar macrophages obtained from C57BL/6 mice and BALB/c mice were reported
to respond differently to acute treadmill running. C57BL/6 mice are prototypical
Th1 strains, whereas BALB/c mice are Th2 strains. In this study, unlike M2 bronchoalveolar macrophages from BALB/c mice, M1 bronchoalveolar macrophages
from C57BL/6 mice did not increase phagocytosis of unopsonized particles after
an acute bout of treadmill exercise, nor did they increase expression of
macrophage receptor with collagenous structure (MARCO). The studies cited
above suggest that exercise training in mouse models may shift the cytokine
milieu to be representative of M1 macrophages.
Exercise-Induced Macrophage Signaling Triggers Specific Anti-Tumor
Mechanisms
It is known that macrophages and MDSCs cross-talk in the cancer microenvironment. It is possible that cytokines specific to both cell types, and that are responsive to acute or chronic bouts of exercise, may represent an immune signature
for exercise-induced immunomodulation in the cancer microenvironment. That is,
the balance of these cytokines may indirectly reflect changes in the macrophage
phenotype in the tumor microenvironment. For example, it was reported that
acute exercise increases serum IL-12 in elite female soccer players, when blood
was drawn 15-20 minutes after a soccer match (2). It appears that to elicit increases in this cytokine, the exercise must be done at an intensity that could be considered vigorous. Increases in serum IL-12 were observed 24 hours after cycle
ergometry was performed at a high intensity (70% of VO2max), but were not
observed when exercise was performed at moderate intensity (55% of VO2max)
(17). Therefore, these human studies suggest that vigorous exercise may elicit an
increase in serum IL-12. While the source of this cytokine is unknown, it is possible that it may be produced by macrophages. While speculative, regular exercise
training may induce IL-12 production in the tumor microenvironment, which
enhances the release of IL-15 in TAMs and subsequently, recruits NK and CD8+
cells to aid in cancer regression (59).
Exercise also increases the release of extracellular HSP70 from liver into
the circulation (45). The secretion of this molecular chaperone has immunomodulatory implication, for it is known that HSP70 binds to human monocytes and upregulates the expression of TNF-, IL-1 and IL-6 (3). We hypothesize that exercise may: i) activate the heat shock response as a means to enhance macrophage
surveillance against potential danger, which in this case are the transformed
epithelial cells or ii) induce a DAMP response in stressed tumor cells, potentially
by increasing HSP70, which can recruit and activate M1 macrophages for phagocytosis. The anti-cancer response involving DAMP could involve toll-like receptor (TLR) signaling. TLR-4 is a transmembrane protein expressed on monocytes,
macrophages and dendritic cells, that functions as a pattern recognition receptor
in response to recognition of DAMPs, such as those expressed by bacterial
lipoproteins, or other danger signals (18). One such danger signal would
include cancer cells. Indeed, the innate immune system is capable of recognizing
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Exercise, Breast Cancer, Macrophages 169

cancer cells via TLR activation and the subsequent production of anti-cancer molecules, such as IFN- (9). The activation of TLRs via ligand binding then results
in their binding to intracellular adaptor proteins such as MyD88, and recruits
other proteins involved in the inflammatory process, such as IL-1R-associated
kinase (IRAK)-1, as well as inducing the production of inflammatory cytokines
such as IL-1 and TNF-, both of which are transcriptional upregulators of iNOS
and also products of M1 macrophages (47). However, cancer cells can induce
immune tolerance in monocytes by down-regulating the expression of IL-1 and
TNF- by activation of IRAK-M, a negative regulator of the inflammatory
response (9). This activation of IRAK-M appeared to be dependent on TLR4 signaling as well, since pre-incubation of human monocytes with TLR4-specific
antibodies reduced IRAK-M induction in a dose-dependent manner (9).
In addition to its role in cancer cytotoxicity, TLR4 acts as a functional
receptor for serum amyloid A3 (SAA3) on lung endothelial cells and
macrophages during the pre-metastatic phase, suggesting that TLR4 expression is
up-regulated in TAMs such that they are then recruited to pre-metastatic sites
(23). These studies illustrate a mechanistic role for TLR4 in mediating anti-cancer
response in innate immune cells, as well as in the chemoattractant response for
TAMs to condition the pre-metastatic site for eventual metastasis. These two roles
appear to be juxtaposed to each other, such that TLR4 signaling may be detrimental in terms of priming the pre-metastatic site for eventual metastatic colonization,
and yet, TLR4 signaling is involved in the activation of the M1 phenotype. To
address this dichotomy, it may be required to consider whether TLR4 signaling in
a pro-inflammatory cancer microenvironment is associated with a better or poorer
clinical prognosis. From a clinical perspective, it was found that physically active
and exercise-trained individuals have lower monocyte expression of TLR4 (18),
suggesting that physical activity may exert an anti-inflammatory response via
TLR4 downregulation in monocytes. Curiously, physically active individuals also
have lower blood concentrations of inflammatory cytokines such as IL-1 and
TNF- (34). In addition, Timmerman and colleagues (55) also reported that combined resistance and endurance training resulted in a reduction in percentage of
CD14+CD16+ inflammatory monocytes in circulation as well as reduced LPSstimulated TNF- production in whole blood cultures of elderly men and women.
These reports of exercise-induced down-regulation of TLR4 expression and
inflammatory cytokine production are not incompatible with the prevailing view
that exercise or physical activity improves innate immunity and reduces inflammation (40). In the context of breast cancer, it may mean that in the pre-initiation
phase of carcinogenesis, macrophages present in the breast microenvironment
should be of the M2 phenotype. This assertion is supported by findings that
macrophages are involved in the remodeling of the mammary tissue during development, lactation and involution (6). A healthy mammary microenvironment likely has an influx of both M1 and M2 macrophages to clear the apoptotic epithelial
cell and assist in the branching of the terminal milk ducts (41). The balance
between M1 and M2 in the mammary microenvironment may favor the development of pre-cancer. Adipocytes in the mammary microenvironment may secrete
pro-inflammatory cytokines to recruit M1 macrophages and increase the susceptibility of mammary cancer risk. To illustrate this point, a chronic inflammatory
state associated with increased expression of M1 macrophages in adipose tissues
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170 Exercise, Breast Cancer, Macrophages

has been reported in diet-induced obesity in mice (33). Conversely, exercise training reduced gene expression of the M1 macrophage marker, CD11c, in adipose
tissue as well as inhibited adipose tissue TLR4 expression in C57BL/6 mice fed a
Figure
high
fat3.diet (28). These studies were not reported in the context of cancer cytotoxicity. Since inflammation is observed in the tumor microenvironment, it may

Figure 3: Proposed role of physical activity and exercise on the polarization of

macrophages in the tumor microenvironment. Physical activity preferentially polarizes
tumor-associated macrophages (TAMs) to an M1 phenotype with anti-tumor affects. Lack of
physical activity results in the preferential polarization of TAMs to the M2 phenotype, which
supports tumor growth, local invasion and metastasis.

be possible that each specific tissue microenvironment affects the plasticity of

TAMs differently. Whereas an M1 cytotoxic macrophage polarization is desirable
for the host in the context of cancer cytotoxicity, excessive inflammation, such as
in the case of chronic inflammation, may lead to tissue destruction, DNA damage,
and oxidative stress, which can paradoxically accelerate carcinogenesis and
metastasis (56). Thus, the balance of M1 to M2 macrophages in a normal mammary microenvironment is tightly regulated by their interactions with the epithelial cells and other stromal cells.
Whether an exercise- or physical activity-induced polarization is seen in
TAMs within the breast tumor microenvironment is unclear, but indirect evidence
from the studies described earlier (29, 32,58) suggest that this may be probable,
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Exercise, Breast Cancer, Macrophages 171

as illustrated in Figure 3. In this scenario, physical activity would preferentially
polarize tumor-associated macrophages (TAMs) to an M1 phenotype with antitumor affects, while lack of physical activity would result in the preferential
polarization of TAMs to the M2 phenotype resulting in tumor growth, local invasion and metastasis. It is unclear whether physical activity/ exercise training
reduces macrophage infiltration of the tumor microenvironment. According to
Czepluch et al. (7), young, healthy human subjects undergoing interval training
comprising bouts of running and cycling were shown to have attenuated MCP-1
induced migration of monocytes in vitro. When the subjects were allowed to
recover for 4 weeks after the exercise training period, their serum concentrations
of MCP-1 protein remained depressed. Whether this suggests a global attenuation
of reduced monocyte trafficking is unclear, and the question then, is whether this
outcome is desirable in terms of overall immune function. Certainly, the case for
having reduction in macrophage infiltration of the tumor microenvironment is
desirable, but only when these macrophage become polarized to that of the M2
phenotype. It is possible that individuals that are endurance-trained or physically
active may have reduced monocyte trafficking, which may be concomittant with
lower pro-inflammatory cytokines in circulation. In the event that such individuals are diagnosed with breast cancer, their long-term training status may result in
a reduction of macrophage infiltration of the tumor microenvironment, and therefore, may also result in a reduction in the quantity of M2 macrophages being
polarized. Alternatively, trained individuals may simply have a better ability to
resolve M1-type inflammation during the different stages of mammary development, and this ability to down-regulate inflammation could be a protective factor
in itself.

SUMMARY
This review has discussed the effects of physical activity and aerobic exercise on
the biology of breast cancer and the possible modulatory effects on TAMs. Not
much is known about other forms of physical activity and exercise training, such
as the impact of occupational and household physical activity, swimming, weight
lifting etc. For individuals with limited access to recreational physical activity, it
may be more applicable to determine whether being physically active at work or
doing household chores could provide improved immuno-modulation of TAMs.
Some crucial questions remain in order to elucidate the role of physical
activity/or exercise on TAMs: i) does exercise training and/ or physical activity
reduce the number of monocytes recruited to the cancer microenvironment, ii)
does exercise training and/ or physical activity alter the phenotype of
macrophages within the cancer microenvironment, but not the trafficking/ recruitment of monocytes to the specific cancer microenvironment? iii) What is the optimal dose of physical activity or exercise training in eliciting a beneficial
macrophage polarization response? iv) Are there differences in macrophage
polarization in the pre-cancer and cancer microenvironment? Addressing these
questions would allow investigators to enhance the knowledge of clinically relevant markers of prognosis, and determine whether physical activity and exercise
training can be used routinely as primary or adjunctive prevention methods to
modulate these markers.
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172 Exercise, Breast Cancer, Macrophages

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