Introduction
The positive influence of exercise on cancer has been shown in multiple contexts.
For
instance, exercise may prevent the onset of colon cancer and improve overall quality
of life in patients with various cancer types while also reducing side effects
caused by medication, such as fatigue [1]
[2]
[3]
[4]
[5]. Additionally, in vivo
studies suggest that exercise might inhibit tumor growth itself [6]. However, the underlying mechanisms of
these effects as well as the cause of slowed tumor growth through exercise remain
to
be elucidated [7]. One explanatory approach
toward this topic is changes within the surroundings of the tumor itself, the
so-called tumor microenvironment (TME) [8].
The TME surrounds the tumor and consists of nonmalignant as well as malignant cells.
The interactions between these various cell types create the TME [9]. While the cells that make up the TME
vary between individuals as well as cancer types, the main components are the
extracellular matrix, immune cells, the vascular system, and stromal cells [10]. The TME is an important contributor to
metastasis, tumor formation, and therapy response. It plays a role in each step of
tumorigenesis, from ensuring cancer cell survival in the early stages to cell
evasion in the later stages [11]. The tumor
influences the TME to favor vascularization and evade the body’s immune response,
and depending on the type of immune cells within the TME, they can either inhibit
tumor growth or promote inflammation and thereby favor it [7]
[11]. Furthermore, the efficiency of therapies depends on the type of
immune cells in the TME [12]. As the
composition of the TME may determine the outcome and alter the prognosis, it is
favorable to find ways in which it can be influenced [13]. In this review, the components of the
TME are not described in detail as a review on this topic has been previously
published [11].
Changes in the TME are an important factor in tumor regulation and can be caused by
exercise [14]. As there are strong
indications that exercise can influence tumor growth, changes in the TME may be one
important aspect [15]. Four known entities
can alter the TME through exercise. These are vascularization, the immune system,
cancer cell metabolism, and myokines [7]
[16]. While recent reviews on
the topic have focused on the changes in the TME as a whole, to our knowledge there
are no reviews focusing on cancer-muscle crosstalk concerning the TME. In recent
years, there have been a number of studies on cancer-muscle crosstalk, which evokes
the necessity to summarize these findings to further concentrate on the direct
influence of muscle activity on changes in the TME and therefore possibly tumor
growth [8].
Myokines are proteins that are released by contracting skeletal muscles and function
in a similar way to hormones. Some are also classified as cytokines. They play a
role in the prevention of multiple chronic diseases, e. g., breast cancer, type 2
diabetes and cardiovascular diseases. While these are fundamentally different
diseases, there appear to be similar underlying mechanisms that can be influenced
by
myokines [17]. To date, only a few myokines
have been identified and connected with a specific function that can be executed in
an endocrine, paracrine or autocrine manner [18]. Myokines are involved in various communication pathways, including
muscle-organ crosstalk and metabolism as well as vascularization [7]. Involvement in other pathways is very
likely. First hints toward the effects that muscle activity has on cancer were
presented in a study that showed that patients with higher muscle strength had a
lower risk of developing cancer compared to patients with lower muscle strength
[19]. Aerobic exercise has been
suggested to increase vascularization in previously oxygen-low areas of the tumor,
which can enhance the immune and drug response [8]. Myokines influence the transcription factors responsible for
vascularization; therefore, exercise can normalize vascularization and metabolism
within the TME [7].
While the number of known myokines is within thousands, the most prominent ones that
are likely to influence the TME will be discussed in this review [18]. The effects of myokines can be local or
systemic, thereby affecting cells directly and indirectly [20]. Most myokines show effects within the
muscle tissue, but the ones that enter the bloodstream can have direct as well as
indirect effects, depending on the target cell via the bloodstream. Myokines can
influence immune cells and have an indirect effect on tumor cells via various immune
cells, or they can have a direct effect if they come in contact with the tumor cells
[16]
[21]
[22]. Therefore, one can
assume that there are direct and indirect effects on the TME [18]. This distinction will be used as a
structure to describe the effects of myokines on the TME.
Myokines and their influence on the TME
Interleukin-6
The most popular and first discovered myokine is IL-6, which is involved in
pathways that regulate muscle hypertrophy as well as cellular oxygen uptake and
fat metabolism [18]. In addition to its
metabolic function, IL-6 is also a key player in chronic and acute inflammation.
In acute inflammatory processes, IL-6 stimulates the production of most proteins
whose increase marks the beginning of an acute inflammatory response [40]. Overall, the effect of IL-6 in
acute inflammation is preservative, as the amount of anti-inflammatory cytokines
remains intact while pro-inflammatory cytokines are repressed. Normally, IL-6
binds to the membrane-bound nonsignaling IL-6 receptor α (IL-6Rα). The resulting
complex can then bind to the signal-transducing subunit glycoprotein 130
(gp130), which is expressed on most cell types. This process actively limits the
IL-6 pathway, as only two cell types, hepatocytes and leukocytes, express
IL-6Rα. Apart from the usual pathway, IL-6 can bind to soluble interleukin-6
receptor α (sIL-6Rα) [41]. This
receptor is usually membrane-bound but can be found in fluids after being shed
from neutrophil membranes in highly inflammatory environments. The resulting
IL-6/IL-6Rα complex favors chronic inflammation by promoting the shift of
neutrophils into monocytes [40]. The
soluble complex also binds to gp130, and as the local restriction is forfeited,
IL-6 signaling can take place in every cell [41]. In the context of inflammation, IL-6 is therefore a two-sided
sword, as it mediates the transition from acute to chronic inflammation by
interacting with the sIL-6Rα receptor. While it exhibits anti-inflammatory
properties in the acute response, it promotes inflammation in chronic events
[42]. In chronic inflammatory
diseases, IL-6 is therefore already used as a target for treatment [43].
In cancer, IL-6 generally has a negative impact, as its signaling is connected to
disease progression in humans and mouse models. Among these negative impacts are
the avoidance of apoptosis, favoring migration and metastasis as well as
angiogenesis. The vasculature of a tumor corresponds to its malignancy, and the
process of angiogenesis in tumors diverges from normal angiogenic processes
[44]
[45]. The vasculature of a tumor is
generally more unstable and unorganized than healthy vasculature [45]. Vascular endothelial growth
factor-A (VEGF-A), a promotor of early-stage angiogenesis, is highly available
in the TME, as it is produced directly by tumor cells [46]. IL-6 has been shown to favor
angiogenic processes by upregulating vascular endothelial growth factor (VEGF)
via the signal transducer and activator of transcription 3 (STAT3) pathway [47]. In the TME itself, IL-6 favors a
tumor-friendly environment, but similar to inflammation, IL-6 can also have a
positive effect in cancer [48]. In an
indirect manner, IL-6 can influence the response of T cells toward an active
immune response. Janus kinases (JAKs) within the TME are activated as part of
the IL-6 pathway, which results in STAT3 signaling, which will be discussed in
more depth later on. Downstream of this pathway, multiple transcription factors
can be activated that navigate the pro-tumorigenic IL-6 response [41].
According to current knowledge, the origin of IL-6 in the TME is tumor cells
themselves, CD4+ T cells, stromal cells, and macrophages [41]. IL-6 levels can also be increased
in the serum. The main source here is contracting muscles [49]. For example, an acute endurance
exercise intervention led to an increased IL-6 concentration in the serum of men
who have lifestyle risks for colon cancer. Colon cancer cells were treated with
this serum, and decreased proliferation was observed. The authors suggest that
cancer cells show enhanced DNA repair when they are exposed to exercise
regularly. A sign or this suggestion is the fact that the effects of IL-6 on
colon cancer cells were dependent on the dose with which they were treated [50]. Whether IL-6 that is released into
the serum has an effect on the TME remains to be explored but appears plausible,
as it is likely that sIL-6Rα is present as a binding factor [51]. Therefore, chronically increased
IL-6 levels in serum may increase tumorigenesis [52].
Direct effects
IL-6, when located in the TME, can have multiple effects, such as STAT3 signaling
activation and other metastasis-promoting effects [53]. STAT3 signaling by IL-6 can
influence gene expression in cancer cells. Soluble IL-6 forms a complex with its
receptors, which can induce STAT3 signaling via activation of JAK. Activated
STAT3 can change the gene expression of the cell, which will lead to
anti-inflammatory gene transcription via membrane-bound activation but
pro-inflammatory transcription if the activating IL-6 complex is soluble as it
is in the TME. Soluble IL-6 in the TME will therefore directly change gene
expression in cancer cells to favor an inflammatory environment, which
contributes to cancer progression [54].
As previously mentioned, IL-6 in the TME can have multiple sources. In addition
to the cell types that were mentioned, carcinoma-associated fibroblasts (CAFs)
can be a main source. CAFs that produce IL-6 are suspected to be the main cause
of epithelial-mesenchymal transition (EMT) [55]. EMT is a process that is necessary for embryogenesis, wound
healing, stem cells, and cancer progression and is characterized by cell
differentiation [56]. During this
differentiation, epithelial cells that are immobile and interact with other cell
basement membranes transition into mesenchymal cells that can move freely. This
new phenotype enhances the ability of cells to migrate [57]. In cancer, this process favors
metastasis and drug resistance [58].
During EMT, cell–cell adhesions are loosened through genes whose transcription
factors are induced by different processes [57]. Factors that induce EMT include cytokines and other soluble
factors [59]. In breast cancer, an EMT
phenotype can be induced, and IL-6 has been identified as a direct inducer of
this phenotype in MCF-7 cells. In this context, the MCF-7 cells produced IL-6
themselves, leading to a feedback loop. Additionally, proliferation was
increased. E-cadherin, a protein in the cell membrane, is responsible for
cell–cell adhesion, and its absence can cause elevated invasiveness in cancer
cells. In the presence of autocrine IL-6 in MCF-7 cells, a complete halt of
E-cadherin expression was observed [60]. The expression of gene tumor protein 3 (TP53), which encodes tumor
suppressor protein p53, is also influenced by IL-6 via the IL-6/JAK/STAT3
pathway. Similar to E-cadherin, p53 expression is attenuated by IL-6 originating
from CAFs via ubiquitination. This results in chemotherapy resistance against
the drug doxorubicin in prostate cancer cells (LNCaP) and possibly against other
chemotherapies by resisting cell death [61].
Indirect effects
The indirect effects of IL-6 on the TME mostly revolve around its influence on
the immune system [62]. Similar to the
IL-6-driven inflammatory response, the influence of IL-6 on the immune system in
a cancer context can be just as equivocal [41]. Recently, the positive effects of IL-6 were highlighted. As a
part of this response, the effect of IL-6 occurs in the lymph nodes and
modulates the immune system [63]. The
activated immune cells then travel to the TME and influence it locally. IL-6 can
modulate the T-cell response by enhancing the survival and proliferation of
leukocytes. Additionally, IL-6 favors the transport of antitumor T cells toward
the TME [41]. While the positive
properties of IL-6 in a tumor response are still to be discovered, there is
recent progress in understanding. It was shown in a mouse model that animals
with access to aerobic training exhibited slower tumor growth, which was linked
to increased CD8+ T-cell metabolism induced by muscle activity. One
can therefore assume that exercise can shift the IL-6 response in tumors toward
a positive response [64]. In general,
infiltration of the TME with T cells favors a good prognosis. CD8+
cells can differentiate into interleukin-21 (IL-21)-producing CD8+
cells via IL-6-induced STAT3 signaling, which supports B cells in viral
responses [65]. In the context of
chronic inflammation, forkhead box protein P3 (Foxp3+)CD8 + cells develop in the
presence of IL-6 and suppress autoimmune responses [66].
T-cell immunity can also be reduced via IL-6 signaling. IL-6, as a soluble
factor, increases the number of myeloid-derived suppressor cells (MDSCs) in
vitro. These cells are an immature form of myeloid cells and can inhibit innate
and adaptive immune responses. In hepatocellular carcinoma (HCC), the number of
MDCs increased through IL-6 signaling and resulted in a reduction in T-cell
immunity. This mechanism causes cancer progression. It is important to note that
the authors mention a strong hint toward this mechanism but that further
experiments are needed to show a direct link [67]. Another example of the negative effects of STAT3 signaling via
IL-6 was found in colorectal cancer. STAT3 phosphorylation by IL-6 in the
presence of transforming growth factor β (TGF-β) in colorectal cancer caused the
differentiation of CD4+ cells into Th17 cells, which can cause
disease progression by onco- and angiogenesis [54]. In a study with colorectal cancer
patients, a positive correlation was found between STAT3+ cells in
the TME and patient survival. The authors also showed that IL-6+
immune cells were found significantly more often in early-stage tumors than in
later-stage tumors [68]. Multiple mouse
model studies showed that tumor growth is either suppressed or slowed when mice
exercised prior to tumor injections. The authors found that the slowed tumor
growth rate correlated with natural killer cell (NK cell) infiltration within
the tumor. In further studies, they found that this effect is caused by acute
IL-6 increases, as NK cells are IL-6 sensitive, and elevated IL-6 levels were
shown in serum after acute intervention. Therefore, the authors suggest that the
acute rise in IL-6 that causes an acute inflammatory process may inhibit tumor
growth, while repeated exercise bouts before the disease can slow or prevent
tumor progression by immune system activation [69].
Oncostatin M
OSM belongs to the family of IL-6 cytokines, as it can also bind to gp130
complexes [70]. In addition to gp130
complexes, OSM can bind to OSMRβ chains, which are expressed on a variety of
cells [71]. While OSM is produced by
multiple cells of the immune system, such as macrophages and dendritic cells, it
is also secreted by skeletal muscle, which classifies it as a myokine [70]
[72]. It is involved in multiple processes, such as liver development
and blood cell production, and has been suggested as a target for treatment in
common diseases, as OSM is also involved in the inflammatory response and can
prevent neural cell damage [72]
[73]. In cancer, OSM can promote cancer
progression but was originally regarded as inhibitory [74].
OSM in the TME contributes to cancer progression by recruiting M2 macrophages
into the tumor environment and by altering the phenotype of CAFs. In general,
elevated OSM levels in serum as well as in the TME have been associated with
disease progression in different cancer types [75]. While aerobic exercise increases
OSM concentration in muscle tissue, it has been shown that OSM concentration
also increases in serum after aerobic exercise in mice that were previously
injected with breast cancer cells [73]
[76]. In cancer cells,
the oncostatin M receptor (OSMR) can be overexpressed. This overexpression leads
to increased OSM signaling, which will cause angiogenesis, invasiveness, and
cell migration. OSMR overexpression will therefore favor disease progression. As
OSM binds to OSMR, STAT3 signaling is activated, and gene transcription of
VEGF-A and transglutaminase 2 (TGM2) is induced. VEGF-A induces angiogenesis,
while TGM2 causes cell migration [77].
An in vitro experiment with triple negative breast cancer cells that were
cocultured with neutrophils suggests that neutrophils in the TME will increase
OSM production, which will then promote metastasis and tumor progression [70]. Similar to IL-6, OSM concentration
appears to increase in serum and tumor tissue after exercise in mice [76].
Direct effects
In the TME, OSM has been brought into the context of EMT and was identified as
the largest contributor toward the attainment of cancer stem cell
characteristics (CSCs). Similar to IL-6, OSM can bind to STAT3. OSM/STAT3
signaling will then lead to an accumulation of mothers against decapentaplegic
homolog 3 (SMAD3) in the nucleus [78].
SMADS are intracellular proteins that function as transcription factors that are
activated by TGF-β and control the transcription of TGF-β target genes in a
cofactor-dependent manner [79]. The
altered transcription by OSM/STAT3 signaling favors gene transcription that will
enhance EMT as well as CSCs. This increases the invasiveness and drug resistance
of the tumor [78].
Indirect effects
Overexpression and promotion of tumor growth by OSM in vitro was observed in a
study by Simonneau et al. [80] in skin
cancer. In the same study, the authors showed that tumor size in vitro and the
polarization of M2 macrophages are reduced if OSM is absent, which suggests that
OSM is an indirect promotor of cancer progression. The authors of a 12-week
intervention study on prostate cancer patients analyzed serum myokine levels
before and after the intervention and found a significant rise in OSM serum
concentration, which correlated with lean body mass. The intervention consisted
of aerobic and resistance training. In cell culture, the growth rate of cells
with the conditioned serum slowed. The authors mention, however, that a direct
connection between the rise of myokines and slowed cell growth could not be
shown [30]. OSM was identified as a
promoter of breast cancer and metastasis by directing stromal intracellular
crosstalk between cancer cells, immune cells, and cancer cell-associated
fibroblasts [81]. In the context of
this study, the authors took OSM produced by myeloid cells into account and
found a feedback loop between these cells and cancer cells with OSM receptors.
In summary, the authors state that the role of OSM within the TME remains
unclear, while it is also suggested that OSM/STAT3 signaling is a promising
target to reduce drug resistance [78].
SPARC
Another myokine that was observed in an intervention study is SPARC [82]. SPARC is a common protein within
the extracellular matrix (ECM) that can be found in the TME. SPARC was described
as a family of closely related proteins that have multiple functions in adult as
well as embryonic tissue [83]. As the
authors reported, SPARC can influence the cell cycle in late phases,
vascularization, matrix mineralization, and cell adhesion. Its role is not
clearly understood, but according to the current literature, the role of SPARC
within the tumor is dependent on the cell type and the tissue in which the tumor
lies [84]
[85].
As a protein of the cellular matrix, SPARC regulates the interaction among cells
and the communication between cells and the extracellular matrix (ECM). In
cancer, SPARC influences cell–cell adhesions and can therefore increase the
migratory properties of cancer cells, which may lead to metastasis [86]. Low SPARC levels in a murine
melanoma model in vitro and in vivo appear to reduce invasiveness and cell
migration, supporting the previous statement [87]. Contrary to this finding, SPARC is suspected to inhibit tumor
progression and metastasis in bladder carcinoma, partly by limiting the
inflammatory response [88].
Direct effects
There are no known receptors of SPARC in humans, but there are a few suspicions
on how SPARC might directly influence cancer cells [89].
An antibody study with different human tissues was conducted to determine the
amount of SPARC within those tissues. The most prominent findings were that
SPARC appeared to be binding on the ECM rather than being incorporated in it.
Additionally, it was shown that the SPARC concentration is higher in malignant
tissues [83]. SPARC can directly bind
to collagen and interacts with factors such as VEGF, fibroblast growth factor
(FGF), and TGF-β [85].
Indirect effects
In biopsies of colon cancer patients, SPARC expression correlated positively with
VEGF, and low SPARC expression was associated with a poor outcome [90]. In renal cell carcinoma, SPARC is a
downstream effector of TGF-β, and its expression is increased by TGF-β
concentration. In this context, matrix metalloproteinase-2 (MPP2) expression was
increased in vitro, which promotes invasion and therefore metastasis [91]. On the other hand, SPARC normalized
the TME of ovarian cancer cells in vitro and in vivo via downregulation of VEGF
[92]. SPARC is released through
acute as well as longitudinal training interventions. An increase in SPARC in
the plasma was shown in mice as well as humans, while gene expression after
acute and longitudinal training was also elevated [24]. Plasma levels of SPARC appear to
return to pre-exercise levels within 6 hours in mice and humans [3]. In prostate cancer patients
specifically, no elevation in serum SPARC levels was observed, but a trend could
be seen after a 12-week exercise training intervention [30]. The inhibitory and promoting
properties of SPARC may be dependent on the origin or the cell type, which can
be malignant or stromal. Therefore, it may be beneficial to involve these
factors in further studies [90].
In summary, the role of SPARC within the TME remains to be elucidated and may be
altered by multiple factors, while it is clear that SPARC expression is
influenced by exercise and plays a role in cancer progression [82]
[85]
[90].
Irisin
Irisin was first described as a hormone that is secreted after exercise in mouse
models as well as humans through fibronectin type III domain-containing protein
5 (FNDC5) cleavage [93]. FNDC5 is a
transmembrane protein that is located in multiple tissues, one of which is
skeletal muscle. Upon physical exercise, the extracellular part of the protein,
which is irisin, is cleaved from FNCD5 and will enter the bloodstream, but it is
unclear what causes this cleavage [94]
[95]. Additionally, FNDC5
expression is upregulated by peroxisome proliferator-activated receptor γ
coactivator 1α (PGC-1α), which is an exercise-induced coactivator. In humans and
mice, irisin levels in serum increase after exercise, while the increase is
higher in trained humans, while irisin levels decrease with age. Additionally,
irisin injections may induce muscle hypertrophy in mice [96]
[97]. In an acute setting, resistance exercise provoked the strongest
irisin response compared to endurance or combined exercise [98]. In a recent study in which adults
performed an acute high-intensity interval training (HIIT) intervention, irisin
levels in serum increased compared to moderate exercise and control [97]. Interestingly, a meta-analysis
demonstrated that chronic exercise decreases the circulating concentration of
irisin [99].
Myokine was first shown to promote brown fat development in vivo via
mitochondrial uncoupling protein 1 (UCP1) expression [93]. Soon after, irisin became linked
not only to obesity but also to multiple diseases [100]. The link between cancer and irisin
has been drawn, as obesity favors an inflammatory environment that increases
cancer cell survival and proliferation [96]. Recently, the role of irisin in breast cancer was examined [94]. The authors found that tumor
progression relates to decreased irisin levels and that high levels respond to
an increased survival time. Irisin levels also appear to play a role in renal
cancer. FNDC5/irisin levels were tested in the serum of patients and compared to
a healthy control group with an enzyme-linked immunosorbent assay (ELISA). The
study revealed elevated FNDC5/irisin levels in the patient group compared to the
control group [101]. In contrast to
this study, most in vitro experiments have shown that irisin has an inhibitory
effect on cancer progression [102].
Direct effects
Irisin was recently brought into context with exercise and the TME. The
underlying idea is that irisin has a metabolic effect that may be transferable
to cancer cells, as one hallmark of cancer is altered glucose metabolism. This
was tested in vitro with multiple ovarian cancer cell lines. In a time- and
dose-dependent manner, irisin suppressed cell proliferation and migration as
well as the clonogenic potential of ovarian cells, in addition to a heightened
sensitivity toward chemotherapy treatment [103].
An in vitro experiment with breast cancer cells showed that the activity of
caspase-3/7 is increased, while activity of nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-kB) is suppressed after
irisin treatment. This leads to a lower count of breast cancer cells and
decreased cell migration [104].
Caspase-3/7 are both proteases that can directly induce apoptosis and are
therefore important markers, e. g., in cancer drug efficiency [105]. NF-kB summarizes a group of
transcription factors that regulate inflammation as well as cell migration and
other mechanisms that are important in cancer development [106]. Irisin treatment of OC cells
decreased hypoxia-inducible factor-1-alpha (HIF-1α) and VEGF expression,
possibly favoring tumorigenesis. Aside from these observations, an induction of
apoptosis was also observed [103]. In
another in vitro study on pancreatic cancer, ferroptosis, an iron-dependent type
of apoptosis in which reactive oxygen species accumulate, was enhanced when
cells were treated with irisin. These findings suggest that irisin may have a
direct effect on cell death and is therefore an interesting therapeutic target
[107].
Indirect effects
Serum irisin levels decrease in humans with age, while they are increased after
acute exercise interventions but remain unaffected by chronic exercise [108]. In regard to aerobic metabolism
genes, irisin had an inhibitory effect on VEGF expression, while the expression
of other observed genes varied among cell lines. The effects on metalloproteases
are still inconclusive and will need further studies that involve the effect of
different exercise interventions on myokines and cancer cells [103].
BDNF
BDNF is a myokine as well as a neurotrophin that is known to influence multiple
mental disorders [109]. Another
important aspect of BDNF is its metabolic effects. BDNF binds to tropomyosin
receptor kinase B T1 (TrkB. T1) in pancreatic cells and thereby increases
insulin secretion in a murine model. These findings support the notion that BDNF
is regulated not only by hippocampal activity but also by muscle activity and
has a peripheral effect [110]. These
findings are supported by the discovery of increased BDNF serum levels in obese
patients after an eight-week moderate- or high-intensity training intervention
[111]. In contrast, in other
studies, increasing levels of BDNF were detected within the muscle but not the
periphery, leading to the conclusion that BDNF exhibits its function in an
autocrine and paracrine manner, while it may have an effect on peripheral
metabolic activity. While the amount and mRNA expression of BDNF is increased in
muscle through exercise, the effects appear to be local without release into the
bloodstream, which makes an influence on the TME unlikely [25]
[112]. Despite this, there is evidence that BDNF contributes to cancer
progression by increasing metastasis-promoting cell properties, angiogenesis,
and chemotherapy resistance [113]. As
there appears to be no consensus on the effects of BDNF and it is unclear
whether central nervous system or muscle activity causes increased serum BDNF
levels, it remains elusive whether BDNF can have an effect on the TME.
Discussion
Exercise is an important factor in cancer prevention, treatment, and rehabilitation
due to its multiple positive effects on patients. The question that remains
unanswered is which molecular mechanisms contribute to these findings. A summary of
the currently known effects of the myokines presented above is presented in [Fig. 2]. The current literature shows that
myokines are a promising aspect for answering these questions. All myokines that we
described above may contribute to cancer development in different manners, but all
of them need further exploration. Further studies also need to be conducted to
understand which exercise has the greatest impact on the different myokines to
determine which exercise mode is most helpful as supportive cancer treatment and
rehabilitation. As pictured in [Fig. 1],
the serum and plasma levels of myokines are influenced by different types of
exercise. While the majority appears to be more affected by acute exercise, it is
unknown if the alterations in serum or plasma concentration by acute exercise remain
persistent in regularly trained individuals or if adaptions can be observed. This
would mean that repeated training sessions are required to have a direct effect on
the TME, while long-term adaptations may lead to enhanced perfusion through
angiogenesis and therefore a better response towards treatment [8]. This is supposedly caused by chronic
changes in myokine concentration in serum, which can be either elevated or depleted
[17]
[21]
[26]
[108]. Overall, the intensity of exercise may
be related to the levels found in serum, therefore one could assume that overall
high intensities in exercise are favorable in the context of cancer prevention and
rehabilitation [29]. Currently, the acute
effects of myokines appear to be of higher importance.
Fig. 2 The effects of myokines on the tumor microenvironment.
An important question that remains to be answered is whether myokines from the
periphery have a direct influence on signaling pathways within the TME. As a part
of
cancer research, the discovery of new approaches in cancer treatment is imminent.
This includes research directed toward drug resistance as well as the discovery of
new target pathways. One approach toward this goal is to understand the molecular
aspects of the TME and how modulations influence tumor growth. Tumor growth has been
shown to be slowed or inhibited by different modes of exercise in animal studies and
in vitro. As there is no consensus about the exact molecular mechanisms of exercise
on the TME, we propose the approach of investigating the role of myokines in the TME
[74]. In this review, we presented the
most commonly known myokines and their influences on the TME and consequently tumor
growth and progression. It was shown that myokines can have tumor progression as
well as inhibitory effects. These appear to depend on multiple aspects, e. g.,
dose-dependent effects. Additionally, the interactions between myokines themselves
and between myokines and cytokines may contribute to the effects on the TME.
In summary, the findings of this review show tumor progression as well as inhibitory
properties for all myokines discussed. These effects may be dose-dependent, and
exercise can therefore have negative as well as positive effects on tumors. Another
important aspect is the differentiation between acute and chronic myokine effects
in
addition to interactions between myokines and between myokines and other cytokines,
as this can also alter the effects on the TME. Exercise is a promising contributor
to altering the TME, and the inhibitory effects of exercise on cancer have been
demonstrated by in vivo and in vitro studies. Myokines likely contribute to these
effects, which makes them an interesting target to further elucidate the effect of
exercise on cancer disease.
