Every exercise bout matters:

Linking systemic exercise responses to breast cancer controlChristine Dethlefsen, Katrine Seide Pedersen, and Pernille Hojman

AFFILIATION

Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS),

Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark

CORRESPONDING AUTHOR

Pernille Hojman, PhD, MSc.

Senior researcher, group leader

The Centre of Inflammation and Metabolism (CIM) and the Centre for Physical Activity Research (CFAS),

Copenhagen University Hospital, 7641, University of Copenhagen

Blegdamsvej 9, DK-2100 Copenhagen, Denmark

E-mail: phojman@inflammation-metabolism.dk

Phone: +45 35457544

ARTICLE INFORMATION

Word count:

Abstract: 211

Article: 3495

Figures/boxes: 1 figure and 2 boxes

KEYWORDS

Breast cancer, acute exercise, chronic training, systemic factors

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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 guidelines, prescribing 150 minutes 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 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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INTRODUCTION

Within the last years, interest in exercise and physical training of cancer patients has exploded, driven by

consistent epidemiological evidence, proving that regular physical activity is associated with decreased risk

of a range of cancers [3]. Moreover, epidemiological studies show reduced risk of recurrence of several

cancer diagnoses, including breast cancer, in physically active compared to inactive cancer survivors [5]. As

a consequence, huge efforts are being put into conducting large-scale exercise intervention trials in cancer

patients and survivors [6]. 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 [8]. 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 outcomes, 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 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 considered the main candidates as mediators of the exercise-

dependent protection against cancer [12]. 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 factors did not translate into any control of breast cancer cell viability, when

tested in serum incubation cell culture studies [13]. Oppositely, our study highlighted the importance of

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understanding the systemic changes occurring during each individual bout of exercise, as serum collected

immediately after cessation of exercise decreased viability of the breast cancer cells [13].

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 distinct exercise responses are discussed. To narrow the scope of the

review, we only focus on the systemic effects of endurance exercise (physiological adaptations are

discussed 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 literature 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 [14]. 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 [15].

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In premenopausal women, some studies find associations similar to those seen in postmenopausal women

[16], while others suggest that the association between elevated levels of sex hormones and breast cancer

risk is limited to testosterone [17].

At the cross-sectional level, studies have shown that high physical activity levels are inversely correlated

with estradiol and testosterone levels in premenopausal women [18-20]. However, in a large exercise

randomized controlled trial (RCT) 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 [21]. In postmenopausal

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 overweight 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 [22,23]. At the cross-sectional level, physical activity in postmenopausal women

is in some studies correlated with sex hormone levels [24-28], however these correlations are only evident

before adjustment for BMI [24,28], 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 analysed 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 [29].

Insulin

People suffering from type 2 diabetes and/or obesity show increased incidence of many cancers, and have

higher cancer-related mortality [30]. This has partly been explained by insulin resistance with resulting

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hyperinsulinemia, and elevated plasma levels of Insulin-like growth factor (IGF) family members [31,32].

Insulin controls blood glucose levels by inducing peripheral glucose uptake, but also exerts direct anabolic

and anti-apoptotic effects on normal and malignant cells [31,32]. Several studies have shown correlations

between elevated plasma insulin and increased incidence of various cancers, including postmenopausal

breast cancer [33]. In continuation, high levels of insulin have been associated with increased recurrence in

breast cancer survivors [34]. IGF-1 resembles insulin in its stimulatory effects on cell proliferation [35]. 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 [35]. Accordingly, systemic levels of IGF-1 and its binding proteins have been related

to various cancers including breast cancer [36].

A recent meta-analysis showed that breast cancer patients may reduce fasting insulin levels with a mean

difference of -3.46 µU/ml after exercise interventions, however this decrease is dependent on weight loss

[37]. 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.) [38]. 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 [39,40].

A few studies have investigated the IGF-1 axis in relation to exercise in cancer survivors, but the results are

inconsistent [41-43].

Inflammatory markers

Cancer-related inflammation has been included as the seventh hallmark of cancer [44], and the most

prominent inflammatory markers are C-reactive protein (CRP), IL-6, and TNF-α. CRP is an acute phase

protein widely recognized as a sensitive biomarker of systemic inflammation, whereas IL-6 and TNF-α are

pro-inflammatory cytokines stimulating CRP production and a range of other inflammatory processes [45].

Studies have shown that elevated CRP levels are associated with increased risk of cancer, and increased

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levels of CRP are associated with early death after a cancer diagnosis [46]. Moreover, CRP is significantly

elevated in breast cancer patients compared to people without a cancer diagnosis [47-49]. Less conclusive

evidence exists for the involvement of IL-6 and TNF- in cancer risk, but plasma IL-6 has been reported to

be augmented in breast cancer patients [50].

Exercise has shown to reduce systemic CRP levels [51-53], as in extremely well-trained male ultrarunners

displaying 66 % lower CRP levels compared to sedentary male controls [54]. Generally, trained individuals

without a cancer diagnosis have between 18-60 % lower plasma CRP levels compared to controls [51,53-

55]. The response in CRP levels to exercise training is most prominent if the exercise intervention exceeds 4

months, and larger reductions are observed if the subjects are obese [56], diseased with low-grade

inflammation [57], or if the intervention is combined with diet restrictions [58]. Limited data in breast

cancer patients are available, and most studies do not show any changes in CRP during a training period

[51,59-62]. The effects of regular exercise on IL-6 and TNF-α levels are more varied, with studies reporting

attenuated levels with training [63-65], while other studies show no training effect on IL-6 and TNF-α

concentrations [52,66]. 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-inflammatory cytokine

levels. A recent meta-analysis of 160 exercise intervention studies showed no effect on levels of CRP, IL-6 or

TNF-α [38]. Little information is available on the regulation TNF-α and IL-6 in breast cancer patients

, but a meta-analysis in breast cancer survivors has shown no effect of exercise training [37]. 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

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established. Notwithstanding the impact of exercise on body composition, diet restrictions 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 anticancer 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

[13,67,68]. 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 [69,70]. 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 19-69 years of

age [71]. Both sex hormones return to baseline levels within 30 minutes after exercise cessation [71,72].

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Insulin

Generally, insulin levels are recognized to decrease during both moderate- and high-intensity endurance

exercise [73,74]. A study in well-trained athletes found a progressive decrease in insulin levels from

baseline concentrations during incremental exercise, ending at 4-fold lower levels [75]. However in the

recovery period, insulin rapidly increased, overshooting baseline levels 2-fold 5 minutes post exercise [75].

Plasma IGF-1 does not appear to be regulated during acute exercise [71,76]. However, a couple of studies

have shown increases in plasma IGF-1 immediately after high-intensity exercise with decreases 30-90

minutes into recovery comparable to or below baseline values [77,78].

Inflammatory markers

Exercise directly affects the systemic levels of inflammatory markers. During acute exercise, plasma IL-6

levels increase >10-fold [79], 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-,

lowering the systemic inflammation. Indeed, it has been shown that acute exercise is capable of inducing

and maintaining an anti-inflammatory milieu several hours after the exercise bout [80]. Although exercise

has also been described to elicit pro-inflammatory responses and induce increases in TNF-α, IL-1β, and CRP,

this only occurs after strenuous exercise with associated muscle damage [81], 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 [82], and the increase in plasma IL-6 seen during exercise can largely be attributed to

release from the contracting 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 intramuscular glycogen

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depletion triggers augmented IL-6 secretion from the muscle [83]. Since the discovery of IL-6, numerous

other myokines induced by acute exercise have been identified, including ANGPTL-4, MCF-1, CCL2, CX3CL1,

IL-8, IL-15, Irisin, and SPARC [69,84]. 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 [67-69]. Myokines belong to a number

of distinct protein classes, and their potential in 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-β or Wnt signalling.

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 minutes of high-intensity exercise [85],

reaching levels up to >20 times of basal concentrations [85,86]. 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 maintenance of blood glucose levels. Thus, short term

exercise is not thought to increase plasma levels of this glucocorticoid [74,87,88]. Unlike the

catecholamines, cortisol exerts its effect over several hours as its half-life is around 60 minutes [88].

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

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stimulates it [89]. Contrary to the exercise-mediated transient spikes of stress hormones, chronic stress is

characterized by chronically elevated cortisol and catecholamine levels, and observational studies show

that chronic stress might promote breast cancer onset and progression [90]. In line with this, treatment

with β-blockers was recently showed to be positively correlated with breast cancer specific survival in a

large meta-analysis [91]. 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 circulating 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 [87]. This exercise-dependent

mobilization of NK cells was recently shown to be driving the tumor suppressive effect of voluntary wheel

running in mice [70]. In this study, blockade of adrenergic signaling blunted the exercise-dependent

suppression of tumor growth by impeding immune cell mobilization and intratumoral 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

[70]. Also, myeloid-derived suppressor cells (MDSCs) are regulated by pro-inflammatory cytokines, and

these act to suppress the function of the cytotoxic immune cells [92]. MDSCs constitute a significant part of

the tumor microenvironment [93], and are thought to regulate cancer growth and metastasis [94]. Little is

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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 candidates for the protective effect. In contrast, major increases in 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 potentially 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 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 treatment. 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 importance 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

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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 comprising 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. Observational 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 [6,96], underlining the importance of understanding 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 (Figure 1), where every exercise bout

matters, as breast cancer 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,

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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 levels of systemic risk factors, like sex hormones,

insulin, and inflammatory 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 Diabetes (the Danish Council for Strategic Research, grant no. 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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INFO BOXES AND LEGENDS

INFO BOX 1:

INFO BOX 2:

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INFO 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 [2]. 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 [2]. 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 up regulated, facilitating better substrate utilization [2]. 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 VO2peak 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 [10]. At the molecular level, very little information is available on exercise adaptations in cancer patients.

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INFO 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) [1]. 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.

ExosomesExosomes 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 [4]. 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 [7].

miRNAsWithin 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 [9]. 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 [11].

FIGURE LEGEND

Figure 1: Systemic anti-cancer responses arising with endurance exercise 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 cumulative 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.

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