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Every exercise bout matters: linking systemic exercise responses to breast cancer control

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Cumulative epidemiological evidence shows that regular exercise lowers the risk of developing breast cancer and decreases the risk of disease recurrence. The causality underlying this relation has not been fully established, and the exercise recommendations for breast cancer patients follow the general physical activity guidelines, prescribing 150 min of exercise per week. Thus, elucidations of the causal mechanisms are important to prescribe and implement the most optimal training regimen in breast cancer prevention and treatment. The prevailing hypothesis on the positive association within exercise oncology has focused on lowering of the basal systemic levels of cancer risk factors with exercise training. However, another rather overlooked systemic exercise response is the marked acute increases in several potential anti-cancer components during each acute exercise bout. Here, we review the evidence of the exercise-mediated changes in systemic components with the ability to influence breast cancer progression. In the first part, we focus on systemic risk factors for breast cancer, i.e., sex hormones, insulin, and inflammatory markers, and their adaptation to long-term training. In the second part, we describe the systemic factors induced acutely during exercise, including catecholamines and myokines. In conclusion, we propose that the transient increases in exercise factors during acute exercise appear to be mediating the positive effect of regular exercise on breast cancer progression.
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REVIEW
Every exercise bout matters: linking systemic exercise responses
to breast cancer control
Christine Dethlefsen
1
Katrine Seide Pedersen
1
Pernille Hojman
1
Received: 13 January 2017 / Accepted: 20 January 2017
ÓSpringer Science+Business Media New York 2017
Abstract Cumulative epidemiological evidence shows
that regular exercise lowers the risk of developing breast
cancer and decreases the risk of disease recurrence. The
causality underlying this relation has not been fully
established, and the exercise recommendations for breast
cancer patients follow the general physical activity guide-
lines, prescribing 150 min of exercise per week. Thus,
elucidations of the causal mechanisms are important to
prescribe and implement the most optimal training regimen
in breast cancer prevention and treatment. The prevailing
hypothesis on the positive association within exercise
oncology has focused on lowering of the basal systemic
levels of cancer risk factors with exercise training. How-
ever, another rather overlooked systemic exercise response
is the marked acute increases in several potential anti-
cancer components during each acute exercise bout. Here,
we review the evidence of the exercise-mediated changes
in systemic components with the ability to influence breast
cancer progression. In the first part, we focus on systemic
risk factors for breast cancer, i.e., sex hormones, insulin,
and inflammatory markers, and their adaptation to long-
term training. In the second part, we describe the systemic
factors induced acutely during exercise, including cate-
cholamines and myokines. In conclusion, we propose that
the transient increases in exercise factors during acute
exercise appear to be mediating the positive effect of
regular exercise on breast cancer progression.
Keywords Breast cancer Acute exercise Chronic
training Systemic factors
Introduction
Within the last years, interest in exercise and physical
training of cancer patients has exploded, driven by con-
sistent epidemiological evidence, proving that regular
physical activity is associated with decreased risk of a
range of cancers [1]. Moreover, epidemiological studies
show the reduced risk of recurrence of several cancer
diagnoses, including breast cancer, in physically active
compared to inactive cancer survivors [2]. As a conse-
quence, huge efforts are being put into conducting large-
scale exercise intervention trials in cancer patients and
survivors [3]. However, there are still many challenges in
the design of these studies. This is for instance reflected in
the enormous range of endpoints included in the conducted
exercise intervention trials. In a review of more than 80
published exercise intervention trials in cancer patients, 60
different endpoints were identified as outcome measures
[4]. These endpoints ranged from direct physiological
adaptations to training, such as fitness levels, oxygen
consumption, muscle mass, and strength, across exercise-
related functional outcomes, i.e., functional capacity and
body composition, to biological and psychosocial out-
comes, including quality of life, cancer-related fatigue,
anxiety, and self-esteem.
This diversity in the methodology and selection of
endpoints reflects the genuine lack of understanding of the
Electronic supplementary material The online version of this
article (doi:10.1007/s10549-017-4129-4) contains supplementary
material, which is available to authorized users.
&Pernille Hojman
phojman@inflammation-metabolism.dk
1
Centre of Inflammation and Metabolism (CIM) and Centre
for Physical Activity Research (CFAS), Rigshospitalet,
Faculty of Health Science, Copenhagen University Hospital,
7641, University of Copenhagen, Blegdamsvej 9,
2100 Copenhagen, Denmark
123
Breast Cancer Res Treat
DOI 10.1007/s10549-017-4129-4
biological mechanisms behind the protective effect of
exercise on cancer risk and progression. To this end,
numerous factors have been suggested to be implicated in
the protection. In 2008, McTiernan proposed that exercise-
dependent regulation of the systemic levels of known risk
factors, i.e., sex hormones, insulin, inflammatory markers,
and immune cell function, could be linking exercise to
cancer protection, and these factors have since been con-
sidered the main candidates as mediators of the exercise-
dependent protection against cancer [5]. This assumes that
the factors are both directly driving cancer, as well as
regulated by long-term training. Yet, the causality of this
relationship has not been experimentally established. In
contrast, we recently published a study challenging this
idea, as training-dependent reductions in known risk fac-
tors did not translate into any control of breast cancer cell
viability, when tested in serum incubation cell culture
studies [6]. Oppositely, our study highlighted the impor-
tance of understanding the systemic changes occurring
during each individual bout of exercise, as serum collected
immediately after cessation of exercise decreased the via-
bility of the breast cancer cells [6].
In this review, we describe the role of systemic factors
in the exercise-dependent control of breast cancer. First, we
focus on systemic breast cancer risk factors and their basal
adaptation to long-term training. Secondly, we highlight
exercise factors, which are induced acutely during exercise,
and where accumulating evidence underscores their
importance in exercise-dependent regulation of breast
cancer. Finally, the clinical perspectives of these two dis-
tinct exercise responses are discussed. To narrow the scope
of the review, we only focus on the systemic effects of
endurance exercise (physiological adaptations are dis-
cussed in Box 1).
Systemic breast cancer risk factors and their
adaptations to long-term training
Regular exercise has been suggested to protect against
breast cancer through lowering of systemic levels of known
risk factors, and clinical exercise studies in breast cancer
patients are thus aiming at reducing basal levels of these
with regular training. Conceptually, reducing the levels of
circulating growth factors for breast cancer cells may
improve cancer prognosis, and here, we review the litera-
ture regarding the direct exercise-mediated effects on
baseline values of these systemic components in healthy
people and breast cancer patients.
Sex steroid hormones
In premenopausal women, the majority of estrogens are
produced in the ovaries, while postmenopausal women
primarily produce estrogens in the adipose tissue through
aromatization of androgen precursors. Thus, in the latter
group of women, systemic sex hormone levels and body
composition are tightly correlated [7]. In postmenopausal
women, elevated systemic levels of sex hormones are
associated with increased risk (HR: 2.58 between highest
and lowest quartiles) of breast cancer independently of
BMI [8]. In premenopausal women, some studies find
associations similar to those seen in postmenopausal
women [9], while others suggest that the association
between elevated levels of sex hormones and breast cancer
risk is limited to testosterone [10].
At the cross-sectional level, studies have shown that high
physical activity levels are inversely correlated with estra-
diol and testosterone levels in premenopausal women
[1113]. However, in a large exercise randomized controlled
Box 1 Physiological adaptations to endurance exercise training
Structured exercise training encompasses several changeable parameters, including modality, frequency, intensity, and duration. In particular,
the modality, i.e., endurance or resistance training, represents two distinct adaptive potentials due to their nature of action [89]. Yet for the
untrained cancer patient, engagement in either form of training might promote changes across the entire spectrum of exercise adaptations as
endurance training requires some muscle strength, and likewise resistance training requires some endurance capacity
Endurance training involves longer periods of low to moderate intensity training, activating the skeletal muscle and cardiovascular systems.
Cardiovascular adaptations enhance the reserve capacity for oxygen transport, both at the skeletal muscular, cardiac, vascular, and blood
level, all leading to favorable improvements in VO
2peak
[89]. At the skeletal muscular level, endurance training provokes an oxidative
phenotype by stimulating mitochondrial biogenesis, local angiogenesis, and lactate tolerance. In line with this, proteins involved in ATP
production and the TCA cycle, as well as oxidative enzymes, glucose transporters, and glycogen stores are upregulated, facilitating better
substrate utilization [89]. The energy consumption during exercise training and the changes in metabolic flux lead to favorable changes in
body composition with loss of fat mass. The improved metabolic control is also reflected by increased peripheral insulin sensitivity and
lowering of the cardiovascular risk profile, defined by high blood pressure and elevated blood glucose and metabolic hormone levels. In the
majority of exercise trials conducted in cancer patients, endurance training has been able to increase VO
2peak
and functional capacity, as
well as control body weight in an exercise intensity and volume dose-dependent manner, similar to what would be expected in healthy
people [90]. At the molecular level, very little information is available on exercise adaptations in cancer patients
Breast Cancer Res Treat
123
trial involving 319 women, no regulation of sex hormones
levels could be demonstrated with training, and the authors
explained this by a lack of weight loss [14]. In post-
menopausal women, the effect of exercise on sex hormone
levels is tightly linked to their production in the adipose
tissue, and training-dependent reductions in sex hormone
levels have primarily been observed in overweight women,
who lose weight during the exercise intervention. This is
illustrated by a 1-year training intervention in 170 over-
weight postmenopausal women, where only women, who
lost body weight during the intervention, showed significant
reductions in estrone (-3.8%) and free estradiol (-8.2%).
Also, the levels of free testosterone were dependent on
weight loss with an overall decrease of -6.5% compared to
-2.1% in the control group [15,16]. At the cross-sectional
level, physical activity in postmenopausal women is in some
studies correlated with sex hormone levels [1721]; how-
ever, these correlations are only evident before adjustment
for BMI [17,21], stressing the importance of fat mass in
controlling sex hormone levels in postmenopausal women.
The overall training-induced decreases in sex hormone
levels, regardless of menopausal status, were analyzed in a
meta-analysis, where modest decreases in estradiol and
testosterone (total estradiol: -0.12 pmol/l, free estradiol:
-0.2 pmol/l, testosterone: -0.18 nmol/l) were found in the
exercise intervention groups compared to control groups
[22].
Insulin
People suffering from type 2 diabetes and/or obesity show
increased incidence of many cancers, and have higher
cancer-related mortality [23]. This has partly been
explained by insulin resistance with resulting hyperinsu-
linemia, and elevated plasma levels of insulin-like growth
factor (IGF) family members [24,25]. Insulin not only
controls blood glucose levels by inducing peripheral glu-
cose uptake, but also exerts direct anabolic and anti-
apoptotic effects on normal and malignant cells [24,25].
Several studies have shown correlations between elevated
plasma insulin and increased incidence of various cancers,
including postmenopausal breast cancer [26]. In continua-
tion, high levels of insulin have been associated with
increased recurrence in breast cancer survivors [27]. IGF-1
resembles insulin in its stimulatory effects on cell prolif-
eration [28]. Most IGFs in the bloodstream are bound to
proteins such as IGF-binding protein 3 (IGFBP-3), but a
small fraction of IGF-1 is bioavailable [28]. Accordingly,
systemic levels of IGF-1 and its binding proteins have been
related to various cancers including breast cancer [29].
A recent meta-analysis showed that breast cancer
patients may reduce fasting insulin levels with a mean
difference of -3.46 lU/ml after exercise interventions;
however, this decrease is dependent on weight loss [30].
Another large meta-analysis of 160 randomized controlled
trials, including data from [7000 subjects, showed no
effect of exercise training on fasting insulin in healthy
people without co-morbidities (type 2 diabetes, metabolic
syndrome etc.) [31]. In line with this, other studies have
shown that fasting insulin levels do not change with
exercise training, although the training interventions result
in weight loss [32,33]. A few studies have investigated the
IGF-1 axis in relation to exercise in cancer survivors, but
the results are inconsistent [3436].
Inflammatory markers
Cancer-related inflammation has been included as the
seventh hallmark of cancer [37], and the most prominent
inflammatory markers are C-reactive protein (CRP), IL-6,
and TNF-a. CRP is an acute phase protein widely recog-
nized as a sensitive biomarker of systemic inflammation,
whereas IL-6 and TNF-aare pro-inflammatory cytokines
stimulating CRP production and a range of other inflam-
matory processes [38]. Studies have shown that elevated
CRP levels are associated with increased risk of cancer,
and increased levels of CRP are associated with early death
after a cancer diagnosis [39]. Moreover, CRP is signifi-
cantly elevated in breast cancer patients compared to
people without a cancer diagnosis [4042]. Less conclusive
evidence exists for the involvement of IL-6 and TNF-ain
cancer risk, but plasma IL-6 has been reported to be aug-
mented in breast cancer patients [43].
Exercise has shown to reduce systemic CRP levels
[4446], as in extremely well-trained male ultrarunners
displaying 66% lower CRP levels compared to sedentary
male controls [47]. Generally, trained individuals without a
cancer diagnosis have between 18 and 60% lower plasma
CRP levels compared to controls [44,4648]. The response
in CRP levels to exercise training is most prominent if the
exercise intervention exceeds 4 months, and larger reduc-
tions are observed if the subjects are obese [49], diseased
with low-grade inflammation [50], or if the intervention is
combined with diet restrictions [51]. Limited data in breast
cancer patients are available, and most studies do not show
any changes in CRP during a training period [44,5255].
The effects of regular exercise on IL-6 and TNF-alevels
are more varied, with studies reporting attenuated levels
with training [5658], while other studies show no training
effect on IL-6 and TNF-aconcentrations [45,59]. As for
CRP, studies of longer duration have shown the most
pronounced effects on IL-6, suggesting that prolonged
training interventions are needed for reducing pro-inflam-
matory cytokine levels. A recent meta-analysis of 160
exercise intervention studies showed no effect on the levels
of CRP, IL-6, or TNF-a[31]. Little information is available
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123
on the regulation TNF-aand IL-6 in breast cancer patients,
but a meta-analysis in breast cancer survivors has shown no
effect of exercise training [30]. The average duration of the
included trials in the two meta-analyses were 12 and
16 weeks, and it can be speculated that these interventions
were of too short a duration to have an effect.
Overall, long-term training may decrease systemic
levels of the above-mentioned breast cancer risk factors.
However, the reductions are modest and closely related to
weight loss. Importantly, no direct link between exercise-
dependent reductions in their circulating levels and breast
cancer progression have been established. Notwithstanding
the impact of exercise on body composition, diet restric-
tions are much more potent in reducing excessive body
weight. In this context, controlling caloric intake may be a
more feasible approach for lowering the systemic levels of
these risk factors.
Acute systemic responses in circulating factors
during acute exercise
During the performance of exercise, major but short-lasting
alterations occur in several circulating components, which
in magnitude by far surpass the adaptations seen with long-
term training. In people, who regularly exercise, these
continuous ‘‘boluses’’ of exercise factors have the potential
to impact breast cancer cell biology and viability. Yet, the
anti-cancer effect of these acute systemic responses to
exercise remains a neglected area in the exercise-oncology
research field. Preclinical cancer studies have shown that
the changes induced by acute exercise are capable at
directly inhibiting breast cancer viability, as evident
through stimulation with exercise-conditioned serum or
exercise-induced muscle-derived peptides [6,60,61].
Studies in other cancer diagnoses add to this effect and
stress the importance of this acute response, showing
reduced cancer growth by exercise-mediated increases in
immune cells, epinephrine, and muscle-derived factors
[62,63]. Here, we discuss the acute regulations of the risk
factors reviewed above, as well as other exercise factors
demonstrating strong systemic regulation during acute
exercise, in light of their potential effect in breast cancer
regulation.
Risk factors
Sex hormones
Increases in serum estradiol and testosterone levels are
seen in both pre- and postmenopausal women during
exercise, with changes in their concentrations being
approximately 35 pmol/l for estradiol and 0.2 nmol/l for
testosterone, as reported in an endurance study including
30 females between 19 and 69 years of age [64]. Both sex
hormones return to baseline levels within 30 min after
exercise cessation [64,65].
Insulin
Generally, insulin levels are recognized to decrease during
both moderate- and high-intensity endurance exercise
[66,67]. A study in well-trained athletes found a pro-
gressive decrease in insulin levels from baseline concen-
trations during incremental exercise, ending at fourfold
lower levels [68]. However, in the recovery period, insulin
rapidly increased, overshooting baseline levels twofold
5 min post exercise [68]. Plasma IGF-1 does not appear to
be regulated during acute exercise [64,69]. However, a
couple of studies have shown increases in plasma IGF-1
immediately after high-intensity exercise with decreases
30–90 min into recovery comparable to or below baseline
values [70,71].
Inflammatory markers
Exercise directly affects the systemic levels of inflamma-
tory markers. During acute exercise, plasma IL-6 levels
increase [10-fold [72], and this is followed by an acute
induction in the plasma concentration of anti-inflammatory
markers such as IL-1ra and IL-10. This anti-inflammatory
surge impedes CRP and TNF-a, lowering the systemic
inflammation. Indeed, it has been shown that acute exercise
is capable of inducing and maintaining an anti-inflamma-
tory milieu several hours after the exercise bout [73].
Although exercise has also been described to elicit pro-
inflammatory responses and induce increases in TNF-a,
IL-1b, and CRP, this only occurs after strenuous exercise
with associated muscle damage [74], and exercise is in
general considered anti-inflammatory.
Exercise factors
Myokines
During contractions, skeletal muscle releases peptides,
known as myokines. The best characterized myokine is
IL-6 [75], and the increase in plasma IL-6 seen during
exercise can largely be attributed to release from the con-
tracting muscles. The exercise-induced secretion of IL-6 is
closely associated with low muscle glycogen content, and
exercise of high intensity or long duration, and intramus-
cular glycogen depletion triggers augmented IL-6 secretion
from the muscle [76]. Since the discovery of IL-6,
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numerous other myokines induced by acute exercise have
been identified, including ANGPTL-4, MCF-1, CCL2,
CX3CL1, IL-8, IL-15, Irisin, and SPARC [62,77]. The list
of exercise-induced myokines is continuously growing, and
large-scale omics-based strategies are aiming at elucidating
the entire muscle secretome.
Data on the role of myokines in cancer protection is still
limited; however, a few preclinical studies have been
conducted, demonstrating that muscle-derived OSM and
Irisin can inhibit breast cancer cell viability, while SPARC
reduces tumorigenesis in the colon of exercising mice
[6062]. Myokines belong to a number of distinct protein
classes, and their potential in the control of breast cancer is
reflected by their ability to either activate tumor suppressor
pathways, or antagonize cellular ligands involved in
oncogenic pathways, e.g., TGF-bor Wnt signaling.
Stress hormones
Exercise is associated with induction of stress hormones in
an intensity-dependent manner. Plasma epinephrine and
norepinephrine increase rapidly within the first 15 min of
high-intensity exercise [78], reaching levels up to [20
times of basal concentrations [78,79]. Both epinephrine
and norepinephrine levels rapidly return to baseline levels
after cessation of exercise with the half-life of epinephrine
being within minutes. Cortisol, on the other hand, has
mainly been described to increase with exercise of long
duration, stimulating hepatic gluconeogenesis for mainte-
nance of blood glucose levels. Thus, short-term exercise is
not thought to increase plasma levels of this glucocorticoid
[67,80,81]. Unlike the catecholamines, cortisol exerts its
effect over several hours as its half-life is around 60 min
[81].
The impact of the acute transient peaks in epinephrine
and norepinephrine has not been studied directly in breast
cancer patients, but preclinical studies of human breast
cancer cell lines indicate a dual role of epinephrine, which
at high concentrations inhibits cancer cell growth, while at
low concentrations stimulates it [82]. Contrary to the
exercise-mediated transient spikes of stress hormones,
chronic stress is characterized by chronically elevated
cortisol and catecholamine levels, and observational stud-
ies show that chronic stress might promote breast cancer
onset and progression [83]. In line with this, treatment with
b-blockers was recently showed to be positively correlated
with breast cancer-specific survival in a large meta-analysis
[84]. Noticeably, the chronic stress-induced augmentations
in catecholamine levels are only modest compared to the
increases reported during acute exercise, which may
explain the opposite effects on breast cancer progression of
chronic stress and the spikes in stress hormone levels
induced during acute exercise.
Immune cells
In addition to the systemic factors reviewed above, acute
exercise has major impact on the level and activity of circu-
lating immune cells. However, this response is mainly
mediated through increases in exercise-induced factors, like
the catecholamines and cytokines. Within minutes of exercise
initiation, lymphocytes are mobilized to the circulation, and
following the first shear stress-mediated mobilization,
increases in catecholamine levels mobilize even greater
numbers of immune cells. The most responsive immune cells
to this exercise-dependent mobilization are the natural killer
(NK) cells, followed by T cells and macrophages, and to a
lesser extent other immune cell subtypes [80]. This exercise-
dependent mobilization of NK cells was recently shown to be
driving the tumor suppressive effect of voluntary wheel run-
ning in mice [63]. In this study, blockade of adrenergic sig-
naling blunted the exercise-dependent suppression of tumor
growth by impeding immune cell mobilization and intratu-
moral immune cell infiltration. The study also suggested that
the maturation and activity of the NK cells were enhanced by
wheel running, and that this involved signaling of other
exercise factors, including muscle-derived myokines [63].
Also, myeloid-derived suppressor cells (MDSCs) are regu-
lated by pro-inflammatory cytokines, and these act tosuppress
the function of the cytotoxic immune cells [85]. MDSCs
constitute a significant part of the tumor microenvironment
[86], and are thought to regulate cancer growth and metastasis
[87]. Little is known of the regulation of MDSC with acute
exercise, but the lowering of inflammatory markers with
training or weight loss may reduce the stimulation of MDSC.
In summary, preclinical studies suggest that systemic
changes during exercise may directly inhibit breast cancer
cell progression. The acute exercise-induced changes in the
classical risk factors are minor, and are not plausible can-
didates for the protective effect. In contrast, major
increases in the levels of other systemic components, i.e.,
myokines and catecholamines, have potential to directly
regulate tumor growth. The investigations into the anti-
oncogenic effects of acute exercise are about to gain
momentum, and future studies should aim at evaluating
acutely induced exercise factors in oncology settings.
Besides the myokines and catecholamines, several other
circulating components, e.g., metabolites and exosomes,
are regulated during acute exercise and they could poten-
tially also affect breast cancer progression (see Info Box 2).
Clinical perspectives
Currently, the majority of exercise intervention studies in
breast cancer patients are designed with the purpose of
reducing cancer- and treatment-related symptoms. The
Breast Cancer Res Treat
123
strong epidemiological evidence of the exercise-dependent
reductions in breast cancer risk and progression should,
however, direct a new focus of exercise-oncology studies,
aiming at exploiting exercise directly as anti-cancer treat-
ment. Certainly, if exercise stimulates direct clinical anti-
cancer effects, incorporation of exercise therapy into
standard oncological treatment is highly warranted, and
should be pursued in future trials. For integration of the
most potent training regimens, it is of paramount impor-
tance to identify the exercise-induced factors driving this
protection.
This review challenges the prevailing view of the
exercise-mediated breast cancer control by proposing that
the protective effect lies within every acute exercise bout.
First, the reviewed literature indicates that reductions in the
classical breast cancer risk factors are driven by weight
loss. While weight loss is important in overweight and
obese breast cancer survivors, it may be much easier
obtained by diet restrictions than by regular exercise.
Second, patients with hormone-sensitive breast cancer
receive yearlong treatment with anti-hormone therapy, and
any regulations of hormone levels by exercise in these
patients seem negligible compared to the anti-hormonal
treatment effect. In contrast, major increases in circulating
exercise factors occur during each acute exercise bout.
These repeated ‘‘boluses’’ of potent anti-cancer factors
could be driving the decrease in breast cancer onset and
recurrence by their cumulative effects. Thus, each bout
may provide a small reduction in breast cancer cell growth;
however, if this is repeated numerous times a week for
several months, a substantial anti-oncogenic effect can be
foreseen. To this end, it is of great importance to establish
the most potent acute systemic response, rather than
designing training interventions aiming at inducing weight
loss.
Lastly, breast cancer is a heterogeneous disease com-
prising numerous mutations in hormone receptors and
genetic alterations within each clinical classification, thus
one omnipresent causal relationship between exercise and
breast cancer risk and progression may not exist. Obser-
vational studies in breast cancer patients have pointed
towards a more protective effect of exercise on breast
cancer risk within patients with tumors of the luminal A
subtype [3,88], underlining the importance of under-
standing the actual mechanisms driving the anti-cancer
response to target exercise as cancer medicine.
Conclusion
Exercise induces two distinct systemic exercise responses:
(1) basal adaptations in breast cancer risk factors in
response to long-term training, and (2) repetitive acute
spikes in exercise factors occurring during performance of
each exercise bout. Here, we propose a model (Fig. 1),
where every exercise bout matters, as breast cancer
Box 2 Other exercise factors
In addition to the already described systemic alterations induced by acute exercise, the following components have also showed regulation
during endurance exercise
Metabolites
Metabolites are produced during exercise as the body increases its utilization of fuel substrates. These metabolites are involved in distinct
metabolic pathways, including glycolysis, lipolysis, adenine nucleotide catabolism, and amino acid catabolism. Some examples include
glycerol (lipolysis), alanine, and glutamine (amino acids) [91]. Moreover, small molecules reflecting oxidative stress and modulating insulin
sensitivity have shown to be affected during acute exercise. Some of the most prominent changes occur in molecules involved in glycolysis
and the citric acid cycle and comprise increases in lactate, pyruvate, succinate, and malate
Exosomes
Exosomes are small extracellular vesicles secreted by most cell types, containing various kinds of biomolecules such as peptides, nucleic
acids, lipids, and miRNAs. Exosomes are distinguished from other extracellular vesicles based on their size (20–140 nm in diameter) and
mode of formation (inward budding of the late endosomal membrane, forming intraluminal vesicles within multivesicular bodies). These
multivesicular bodies can then fuse with the plasma membrane, releasing exosomes into the extracellular compartment and circulation [92].
Recently, a study examined the effects of acute exercise on serum release of small extracellular vesicles (referred to as exosomes by the
researchers). It found that both cycling and running in young men led to a rapid and intensity-dependent increase in the amount of small
extracellular vesicles, which was returned to baseline levels 90 min after cycling and 180 min after running [93]
miRNAs
Within the last decade, studies have shown that non-coding microRNAs (miRNAs) are secreted into the circulation. Due to their pivotal role
in controlling cell proliferation, their role in cancer progression is of particular interest. To avoid RNAse degradation, most circulating
miRNAs are encapsulated in exosomes, microparticles, apoptotic bodies, or are associated with RNA-binding proteins or high-density
lipoproteins [94]. Recently, studies have shown that circulating miRNAs are regulated during and after endurance exercise. Immediately
after exercise most circulating miRNAs are downregulated, however, a few hours into recovery their expression levels have shown to be
upregulated [95]
Breast Cancer Res Treat
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prognosis may improve through cumulative effects of each
acute exercise response. Preclinical studies suggest that
these acute systemic changes can control breast cancer cell
viability, and while prominent candidates of the acute
systemic exercise response have been characterized, we are
still in the early phase of fully understanding all the anti-
cancer components of the acute exercise response. In
contrast, long-term training may reduce the levels of sys-
temic risk factors, like sex hormones, insulin, and inflam-
matory markers, but this effect is tightly correlated to
weight loss, and there is a lack of causal evidence proving a
direct link between exercise training and the reductions in
the basal levels of these risk factors.
Acknowledgements This work was supported by grants from the
Danish Cancer Society and the Danish Cancer Research Foundation.
The Centre for Physical Activity Research (CFAS) is supported by a
grant from TrygFonden. During the study period, the Centre of
Inflammation and Metabolism (CIM) was supported by a grant from
the Danish National Research Foundation (DNRF55). CIM/CFAS is a
member of DD2—the Danish Center for Strategic Research in Type 2
Fig. 1 Systemic anti-cancer responses arising with endurance exer-
cise training over time. Schematic model of the systemic anti-cancer
exercise responses: (1) massive but transient spikes during each acute
exercise bout (pink colors), and (2) moderate basal lowering in resting
levels of risk factors over time (purple colors). Based on the reviewed
literature, we propose that the acute systemic response in exercise
factors, e.g., increases in catecholamines and myokines, are driving
the direct exercise-mediated anti-cancer effect through their cumu-
lative effects. Lowering in basal resting levels of risk factors with
long-term training may also be involved in breast cancer control;
however, the effects appear to be mainly mediated by weight loss
Breast Cancer Res Treat
123
Diabetes (the Danish Council for Strategic Research, Grant Nos.
09-067009 and 09-075724).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval This article does not contain any studies with
human participants performed by any of the authors.
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... Chronic reductions in systemic levels of biological risk factors for cancer, including sex hormones, metabolic hormones, and pro-inflammatory cytokines, are thought to be involved. 7,8,9 However, these factors appear to be more heavily impacted by body composition rather than physical activity per se and, from this perspective, it is notable that recent evidence clearly demonstrates that physical activity is associated with a reduction in cancer risk independently of adiposity. 10 Other lines of evidence indicate that transient but marked systemic changes that occur in the hours after each acute exercise bout may also play an important role. ...
... 10 Other lines of evidence indicate that transient but marked systemic changes that occur in the hours after each acute exercise bout may also play an important role. 7 For example, acute exercise is known to mobilise, redistribute, and increase the activity of key cytotoxic immune cell populations including natural killer (NK) and T cells. 11,12 Furthermore, several recent studies have demonstrated that incubation of cancer cells with serum collected after acute exercise can directly impact key hallmarks of cancer cell behaviour in vitro, such as cell proliferation. ...
... Notwithstanding, the findings herein provide support for the notion that repetitive exposure to transient increases in circulating factors after each acute exercise bout may have greater importance in mediating the anti-carcinogenic effects of regular exercise through their cumulative effects, as opposed to chronic adaptations in basal levels of systemic risk factors at rest. 7 From this, it can be speculated that a higher frequency of exercise may be advantageous over accumulating the same volume of exercise on fewer days per week. ...
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Physical activity reduces cancer risk but the underlying mechanisms remain unclear. We meta-analysed the effects of acute exercise and exercise training on serum-stimulated cancer cell behaviours in vitro. Systematic searches of PubMed, Scopus and SPORTDiscus up to February 2021 revealed 8 studies reporting 61 effect sizes eligible for meta-analysis. Standardised mean differences (SMDs) between exercise-conditioned serum and resting serum were pooled using random-effects models. Acute exercise-conditioned serum significantly reduced cancer cell growth (SMD -1.31, 95% CI -1.77 to -0.86, p<0.0001) and colony formation (SMD -2.33, 95% CI -2.66 to -2.00, p<0.0001) in vitro. These growth-inhibitory effects were sustained at 1 to 4 h (growth: SMD -1.56, 95% CI -2.47 to -0.64, p=0.0008; colony formation: -2.57, 95% CI -3.05 to -2.09, p<0.0001) and 24 h post-exercise (growth: SMD -2.62, 95% CI -4.18 to -1.05, p<0.001; colony formation: SMD -2.80, 95% CI -3.42 to -2.18, p<0.0001). In contrast, exercise training-conditioned serum had no effect on cancer cell growth in vitro (SMD -0.14, 95% CI -0.47 to 0.19, p=0.41). Acute exercise promotes transient serological changes that suppress cancer cell growth and clonogenicity in vitro. Repetitive exposure to these factors may play an important role in reducing cancer risk.
... Studies show that exercise can induce multiple physiological changes, including altering the serum composition of factors such as exercise-induced muscle secretomes and catecholamines, which reduces the risk of chronic diseases 13 . Preclinical evidence suggests that exercise might regulate systemic levels of factors, such as local growth factors (IGF1), hormones (insulin and leptin) and inflammatory cytokines (IL-6), which are known to promote prostate cancer growth 14 , with research revealing the connection between exercise-induced alteration of blood contents and tumour growth suppression by directly applying exercise-conditioned serum to various cancer cell lines, including prostate cancer [15][16][17][18][19][20] . ...
... Exercise causes multiple physiological adaptations, such as an increased lean mass (skeletal muscle mass), reduced fat mass, improved cardiovascular fitness and an improved metabolic profile, and these adaptations could contribute to the benefits patients with cancer derive from engaging in exercise 12,33 . Emerging preclinical evidence suggests a role for exercise-induced cell-free or soluble contents in blood (such as cytokines and hormones) in suppressing tumour growth in various cancer cell lines, including prostate cancer, and provides a basis for understanding the role of systemic changes induced by exercise that affect cancer cell biology [15][16][17][18][19][20][44][45][46][47] . ...
... A number of in vitro studies have demonstrated a tumour-suppressive effect of exercise-induced alterations of blood components in multiple cancer cell lines, including prostate cancer 20,[44][45][46] , breast cancer 15,16,23 , colorectal cancer 18,22 and lung cancer 19 (TAblE 1; Fig. 2). These studies showed inhibition of cancer cell viability with serum acquired following an acute bout of exercise [15][16][17][18][19] , whereas serum acquired 2 hours after cessation of exercise failed to suppress cancer cell growth 18 . Notably, some inconsistencies in the outcomes of studies might result from different exercise protocols (mode, intensity and duration), patient populations and cell line types. ...
Article
Exercise is recognized by clinicians in the field of clinical oncology for its potential role in reducing the risk of certain cancers and in reducing the risk of disease recurrence and progression; yet, the underlying mechanisms behind this reduction in risk are not fully understood. Studies applying post-exercise blood serum directly to various types of cancer cell lines provide insight that exercise might have a role in inhibiting cancer growth via altered soluble and cell-free blood contents. Myokines, which are cytokines produced by muscle and secreted into the bloodstream, might offer multiple benefits to cellular metabolism (such as a reduction in insulin resistance, improved glucose uptake and reduced adiposity), and blood myokine levels can be altered with exercise. Alterations in the levels of myokines such as IL-6, IL-15, IL-10, irisin, secreted protein acidic risk in cysteine (SPARC), myostatin, oncostatin M and decorin might exert a direct inhibitory effect on cancer growth via inhibiting proliferation, promoting apoptosis, inducing cell-cycle arrest and inhibiting the epithermal transition to mesenchymal cells. The association of insulin resistance, hyperinsulinaemia and hyperlipidaemia with obesity can create a tumour-favourable environment; exercise-induced myokines can manipulate this environment by regulating adipose tissue and adipocytes. Exercise-induced myokines also have a critical role in increasing cytotoxicity and the infiltration of immune cells into the tumour.
... Obesity, by inducing local hypoxia in the enlarged, VAT, stimulates sustained release of pro-inflammatory mediators (e.g., TNFα) from resident adipose tissue macrophages. Long-term exercise, i.e., more than 16 weeks, attenuates expression of pro-inflammatory markers by reduction in the size of adipose tissue cells [169,170]. Compared to hypocaloric diets, exercise is more effective in reducing adipose tissue mass while conserving the bodies weight [171]. ...
Article
Full-text available
This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer’s disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual’s mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.
... For example, the Women's Intervention Nutrition Study, a randomized trial, showed that women who consumed a low-fat diet had significant weight loss at one and five years and were at a lower risk for breast cancer recurrence than women in the control group (Chlebowski et al., 2006). Relatedly, empirical evidence shows that exercise with weight loss is associated with decreases in proinflammatory biomarkers, including TNF-α (Byers and Sedjo, 2011) and IL-6 (Byers and Sedjo, 2011;Dethlefsen et al., 2017;Neilson et al., 2009;Pakiz et al., 2011). Given that physical activity and dietary behaviors are important contributors of BMI, these findings underscore the importance of targeting these factors to improve breast cancer-related health outcomes for women of low SES. ...
Article
Background Breast cancer is the most common cancer among women in the US, and women of low socioeconomic status (SES) show markedly poorer outcomes than those of high SES. SES may influence health through inflammation, although links between SES and inflammatory biomarkers have not been investigated in women with breast cancer. This study tested the hypothesis that breast cancer patients of lower SES would show higher levels of inflammation than those of higher SES. BMI was examined as a mediator of this association. Methods Women recently diagnosed with early-stage breast cancer (N=194) were recruited before neoadjuvant or adjuvant therapy. Participants completed questionnaires and provided blood samples for immune assessment. SES was indexed by participants’ self-reported education and annual household income, BMI was determined by height and weight measurements, and blood was assayed for inflammatory biomarkers linked with cancer outcomes: IL-6, CRP, TNF-α, and sTNF-RII. General linear models tested associations between SES and inflammation, and mediation models examined indirect effects through BMI. Results Consistent with hypotheses, education status was associated with CRP, (F(2,185) = 4.72, p = 0.001), and sTNF-RII, (F(2,185) = 4.19, p = 0.02), such that lower education was associated with higher levels of both biomarkers. Further, BMI mediated the associations between education and CRP, (95% CIs [-0.62, -0.11; -0.76, -0.21]), sTNF-RII, (95% CIs [-0.09, -0.01; -0.10, -0.02]), and IL-6, (95% CIs [-0.32, -0.05; -0.38, -0.09]). Annual household income was not significantly associated with inflammation (ps > 0.25), and indirect effects on inflammation through BMI were not significant. Conclusions Lower education was associated with higher levels of inflammation in this sample, which may presage poor breast cancer-related and clinical outcomes. SES should inform the development of interventions targeting BMI and inflammation in breast cancer.
... Published research on the benefits of exercise in the cancer population has been dominated by breast cancer studies (1,31,32). To our knowledge, this is the largest screening analysis on the effect of exercise on serum inflammatory biomarkers in the esophageal cancer survivorship setting. ...
Article
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Background The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial. Methods Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA). Results Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05). Conclusions Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer. Impact Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors. Clinical Trial Registration ClinicalTrials.gov (NCT03314311).
... This approach fails to consider if the acute response changes after training. Modulations in hormone, inflammatory and immune factors play critical roles in cancer progression (Dethlefsen et al., 2017;Khosravi et al., 2019) therefore investigating adaptations of these parameters to acute exercise after exercise training is critical. Finally, training studies have compared immune outcomes relative to usual care (Fairey et al., 2005;Hagstrom et al., 2016;Hutnick et al., 2005;Nieman et al., 1994), a logical approach although limited in its inability to make comparisons to the normal response in older adults. ...
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Background Lifetime physical activity (PA) is associated with decreased breast cancer (BC) risk; reports suggest that PA during adolescence contributes strongly to this relationship. PA lowers production of sex hormones, specifically estradiol, or decreases insulin resistance (IR), thereby lowering risk. Overweight Latina adolescents are insulin resistant and exhibit low levels of PA, potentially increasing their future BC risk. Methods 37 obese Latina adolescents (15.7 ± 1.1 yrs) provided measures of PA using accelerometry; plasma follicular phase estradiol, sex-hormone binding globulin, total and free testosterone, dehydroepiandrosterone-sulfate (DHEAS); IR using HOMA-IR; and body composition via DEXA. Partial correlations and stepwise linear regressions assessed cross-sectional relationships between sex hormones, IR and PA. Body composition, and age were included a priori as covariates. Results Estradiol was negatively associated with accelerometer counts per minute (CPM; r = −0.4; P = .02), percent time spent in moderate PA (%MPA; r = −0.5; P = .006), and percent time in moderate or vigorous PA (%MVPA; r = −0.5; P = .007). DHEAS was positively associated with CPM ( r = .4, P = .009), %MPA ( r = .3, P = .04), and %MVPA ( r = .3, P = .04). Other sex hormones and IR were not associated with PA measures. Conclusion This study is the first to show that higher habitual PA was inversely associated with estradiol in obese adolescents.