Chronic low-grade inflammation plays an important role in the pathogenesis of several cancer forms including breast cancer. The pleiotropic cytokine IL-6 is a key player in systemic inflammation, ...regulating both the inflammatory response and tissue metabolism during acute stimulations. Here, we review the associations between IL-6 and breast cancer ranging from in vitro cell culture studies to clinical studies, covering the role of IL-6 in controlling breast cancer cell growth, regulation of cancer stem cell renewal, as well as breast cancer cell migration. Moreover, associations between circulating IL-6 and risk of breast cancer, prognosis for patients with prevalent disease, adverse effects and interventions to control systemic IL-6 levels in patients are discussed. In summary, direct application of IL-6 on breast cancer cells inhibits proliferation in estrogen receptor positive cells, while high circulating IL-6 levels are correlated with a poor prognosis in breast cancer patients. This discrepancy reflects distinct roles of IL-6, with elevated systemic levels being a biomarker for tumor burden, physical inactivity, and impaired metabolism, while local intratumoral IL-6 signaling is important for controlling breast cancer cell growth, metastasis, and self renewal of cancer stem cells.
Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel ...running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.
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•Exercise reduces tumor incidence and growth in several mouse models•Exercise increases NK cell infiltration, thereby controlling tumor growth•Epinephrine mobilizes NK cells and β-blockade blunts the tumor suppression•Exercise-induced muscle-derived IL-6 is involved in NK cell redistribution
The beneficial effects of exercise are countless. Pedersen et al. now link exercise, cancer, and immunity and reveal that exercise decreases tumor incidence and growth by over 60% across several mouse tumor models through a direct regulation of NK cell mobilization and trafficking in an epinephrine- and IL-6-dependent manner.
Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the ...working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth.
Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human ...exercise-conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (
= 20) and healthy women (
= 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability
by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1
mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of β-adrenergic signaling in MCF-7 cells, indicating that catecholamines were the responsible exercise factors. Both epinephrine (EPI) and norepinephrine (NE) could directly inhibit breast cancer cell viability, as well as tumor growth
EPI and NE activate the tumor suppressor Hippo signaling pathway, and the suppressive effect of exercise-conditioned serum was found to be mediated through phosphorylation and cytoplasmic retention of YAP and reduced expression of downstream target genes, for example, ANKRD1 and CTGF. In parallel, tumor-bearing mice with access to running wheels showed reduced growth of MCF-7 (-36%,
< 0.05) and MDA-MB-231 (-66%,
< 0.01) tumors and, for the MCF-7 tumor, increased regulation of the Hippo signaling pathway. Taken together, our findings offer a mechanistic explanation for exercise-dependent suppression of breast cancer cell growth.
.
Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related ...outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P < 0.001), lean body mass (20.6%, P = 0.001), as well as anorexia, impaired muscle strength (22.5% decrease, P < 0.001) and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P < 0.001), maintained lean body mass (P < 0.001) and muscle strength (P < 0.001), reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Purpose
Exercise decreases breast cancer risk and disease recurrence, but the underlying mechanisms are unknown. Training adaptations in systemic factors have been suggested as mediating causes. We ...aimed to examine if systemic adaptations to training over time, or acute exercise responses, in breast cancer survivors could regulate breast cancer cell viability in vitro.
Methods
Blood samples were collected from breast cancer survivors, partaking in either a 6-month training intervention or across a 2 h acute exercise session. Changes in training parameters and systemic factors were evaluated and pre/post exercise-conditioned sera from both studies were used to stimulate breast cancer cell lines (MCF-7, MDA-MB-231) in vitro.
Results
Six months of training increased VO
2peak
(16.4 %,
p
< 0.001) and muscle strength, and reduced resting levels of plasma cholesterol (−18.2 %,
p
= 0.003) and cytokines. Yet, these systemic adaptations had no effect on breast cancer cell viability in vitro. During 2 h of acute exercise, increases in serum lactate (6-fold,
p
< 0.001), epinephrine (2.9-fold,
p
= 0.009), norepinephrine (2.2-fold,
p
< 0.001), and cytokines, including IL-6 (2.1-fold,
p
< 0.001) were detected. Incubation with serum obtained after exercise reduced viability by −9.2 % in MCF-7 (
p
= 0.04) and −9.4 % in MDA-MB-231 (
p
< 0.001) compared to resting serum.
Conclusion
Systemic changes to a 2 h exercise session reduced breast cancer viability, while adaptations to 6 months of training had no impact. Our data question the prevailing dogma that training-dependent baseline reductions in risk factors mediate the protective effect of exercise on breast cancer. Instead, we propose that the cancer protection is driven by accumulative effects of repeated acute exercise responses.
IL-6 is secreted from muscles to the circulation during high-intensity and long-duration exercise, where muscle-derived IL-6 works as an energy sensor to increase release of energy substrates from ...liver and adipose tissues. We investigated the mechanism involved in the exercise-mediated surge in IL-6 during exercise. Using interval-based cycling in healthy young men, swimming exercise in mice, and electrical stimulation of primary human muscle cells, we explored the role of lactate production in muscular IL-6 release during exercise. First, we observed a tight correlation between lactate production and IL-6 release during both strenuous bicycling and electrically stimulated muscle cell cultures. In mice, intramuscular injection of lactate mimicked the exercise-dependent release of IL-6, and pH buffering of lactate production during exercise attenuated IL-6 secretion. Next, we used in vivo bioimaging to demonstrate that intrinsic intramuscular proteases were activated in mice during swimming, and that blockade of protease activity blunted swimming-induced IL-6 release in mice. Last, intramuscular injection of the protease hyaluronidase resulted in dramatic increases in serum IL-6 in mice, and immunohistochemical analyses showed that intramuscular lactate and hyaluronidase injections led to release of IL-6-containing intramyocellular vesicles. We identified a pool of IL-6 located within vesicles of skeletal muscle fibers, which could be readily secreted upon protease activity. This protease-dependent release of IL-6 was initiated by lactate production, linking training intensity and lactate production to IL-6 release during strenuous exercise.
Abstract
Objective: Cancer cells are characterized by a changed cellular metabolism, favoring glycolysis. AMPK, a serine/threonine kinase regulates cellular metabolism, and induces fatty acid ...oxidation and has in regard to this, been shown to suppress tumor cell growth. During physical activity, which is associated with a reduced cancer risk, working muscles secrete myokines, known to activate AMPK. This could indicate a connection between AMPK activity, myokine release from the working muscle, and an anti-cancer response. We hypothesize that exercise-induced myokine secretion causes an anti-cancer response via AMPK activation. Methods: Exercise-induced AMPK activation was studied in two models, 1) A cell study using the two breast cancer cell lines, MDA-MB-231 and MCF-7, incubated with exercise-conditioned serum, representing a myokine pool. Serum was collected from 9 females during a 2 hours cycling bout, and during a subsequent 3 hours rest. Following incubation, cell viability and AMPK phosphorylation was determined in the cells. 2) An In Vivo model, where the two cell lines were injected into nude mice. When the tumors reached 6 mm in diameter, the mice were subjected to 1 hour forced swimming bout, after which the tumors were dissected and analyzed for pAMPK content. Results: 1) Cell study: Two hours of cycling induced a 6-fold increase in serum IL-6, as expected. Incubating cancer cells with this post-exercise serum resulted in a significant reduction in the viability of MCF-7 cells, while no effect on the viability of MDA-MB-231 cells were observed. Preliminary data show increased AMPK phosphorylation in both MDA-MB-231 and MCF-7 cells after incubation with 5% exercise-conditioned serum. 2) In vivo study: 1 hour of swimming resulted in significantly increased AMPK phosphorylation in the MCF-7 tumors. Conclusion: Our preliminary data indicate that exercise-induced factors can cause decreased viability and increased AMPK activity in MCF-7 cells, while MDA-MB-231 cells need further investigation. Acknowledgement: The Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National research Foundation (#02-512-55). This study was further supported by the Danish Medical Research Council and the Lundbeck Foundation.
Citation Format: Grith W. Højfeldt, Christine Dethlefsen, Bente K. Pedersen, Pernille Hojman. Exercise activates AMP-activated protein kinase in breast cancer cells. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5400. doi:10.1158/1538-7445.AM2013-5400
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