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• W2783287506 abstract "Future OncologyVol. 14, No. 4 EditorialFree AccessExercise-induced myokines as emerging therapeutic agents in colorectal cancer prevention and treatmentPriya Roy, Sanjib Chowdhury & Hemant K RoyPriya Roy Section of Gastroenterology, Department of Internal Medicine, Boston University School of Medicine, MA 02118, USASearch for more papers by this author, Sanjib Chowdhury Section of Gastroenterology, Department of Internal Medicine, Boston University School of Medicine, MA 02118, USASearch for more papers by this author & Hemant K Roy*Author for correspondence: E-mail Address: hkroy@bu.edu Section of Gastroenterology, Department of Internal Medicine, Boston University School of Medicine, MA 02118, USASearch for more papers by this authorPublished Online:10 Jan 2018https://doi.org/10.2217/fon-2017-0555AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: antineoplasticcolorectal cancerdiseasomeexerciseexercise-in-a-pillexogenous risk factorshallmarks of cancerin vitro exercise platformmyokinemyokinomeColorectal cancer (CRC) remains the second leading cause of cancer deaths in western countries underscoring the need for more effective preventive and therapeutic strategies. The risk of CRC development can be attributed to both genetic and exogenous (diet, obesity and diabetes, etc.) factors. Importantly, it is estimated that lifestyle factors may be responsible for much of the CRC risk (∼30–60%) [1]. Of these, exercise remains one of the most common and practical modifiable factors with approximately 45% of Americans currently being classified as sedentary (not meeting the recommended 150 minutes/week of moderate-to-vigorous physical activity). This has been implicated in a variety of cancers as noted in a study of 1.44 million adult participants who were dichotomized into those with high versus low leisure time physical activity. The higher exercise group had a decreased risk of colon (hazard ratio: 0.84; 95% CI: 0.77–0.91) and rectal cancer (hazard ratio: 0.87; 95% CI: 0.80–0.95) with comparable effects observed in 12 other cancers including esophageal adenocarcinoma, liver, lung, kidney, gastric cardia, endometrial, myeloid leukemia, myeloma, head and neck, breast and bladder [2].There is a large body of evidence that has confirmed that physical activity reduces CRC risk by about 20–25% in both men and women in a dose-dependent manner [3]. This effect seems equivalent for both CRCs in the proximal CRC with a relative risk (RR; RR = 0.73: 95% CI: 0.66–0.81) and distal (RR = 0.74; 95% CI: 0.68–0.80) despite significant biological differences in these subsites [4]. Physical activity is associated with a decreased occurrence of premalignant lesions (risk reduction for adenomas and advanced adenomas of approximately 15 and 35%, respectively) [3]. There is unequivocal data showing physical activity/exercise exerts a protective effect independent of co-segregating variables such as obesity and diabetes [3]. Moreover, in a randomized controlled trial, moderate-to-vigorous intensity exercise intervention was shown to modestly but significantly reduce the colon crypt cell proliferation patterns in men who exercised at least 250 min/week [5].Along with the cancer preventive benefit, there is emerging evidence that exercise may actually improve survival in patients who have already developed CRC [6]. Physical activity significantly decreased cancer recurrence and CRC-related deaths [7]. There is significant association between prediagnostic physical activity and CRC prognosis after diagnosis in terms of overall, CRC-specific, recurrence-free and disease-free survival [6]. Park et al. noted that exercise and low body-fat mass were significantly correlated with lower rates of colorectal polyp recurrence in the surveillance of CRC survivors [8]. Another meta-analysis reported that physical activity after the diagnosis of CRC was associated with a marked decrease in the pooled relative risk in mortality with a CRC specific mortality of 0.77 (95% CI: 0.63–0.94) and total mortality of 0.71 (95% CI: 0.63–0.81) [9]. Furthermore, exercise therapy may be beneficial for CRC patients during adjuvant treatment. Specific guidelines for physical activity for cancer survivors have been recommended given these wide-ranging benefits.The prescription of exercise as an adjuvant therapy has been reported by prospective cohort studies to reduce the risk of recurrence and death among colon cancer survivors [7,10]. The dose-response nature was nicely demonstrated in the randomized COURAGE exercise trial in which frequent moderate-intensity aerobic exercise elicited favorable prognostic biomarker alterations in patients recently treated for stage I–III colon cancer [10]. However, concerns still remain regarding the feasibility, tolerability and efficacy of compliance of recommended exercise regime in cancer patients suffering from cancer and chemotherapy-related fatigue. Furthermore, compliance with lifestyle modifications in the population has been relatively dismal highlighting the need to develop pharmacological agents that provide similar benefit. For this, understanding the biology of exercise-mediated benefit is critical.Biologically, exercise appears to impact on numerous of the Hanahan and Weinberg's ‘hallmarks’ of cancer including resisting cell death, sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enhancing replicative mortality enhancing angiogenesis, reprogramming energy metabolism and evading immune destruction [3]. There is a myriad of putative molecular mechanisms (metabolic changes, modulating insulin/insulin growth factor signaling, immune alterations and epinephrine release, etc.). While the mechanisms of exercise effect are undoubtedly pleotropic, several lines of evidence suggest that skeletal muscle may have a role. For instance, in a prospective cohort trial with an average of 18.8 years follow-up, those with the lowest and middle third of muscle strength had a higher risk of cancer development when compared with the highest third (1.59 and 1.70 respectively) [11]. From a therapeutic perspective, a provocative report suggested that preoperative psoas muscle strength was a powerful predictor of survival for patients undergoing surgical pancreatic cancer [12]. From a mechanistic perspective, there are intriguing data that suggest skeletal muscle is an endocrine organ secreting cytokines in response to contraction (termed myokines) which may transduce the numerous antineoplastic effects [3].The role of myokines in biology was pioneered in a series of reports from Pedersen and colleagues. This started with the classic discovery of cytokine IL6, which is released from skeletal muscle during exercise [13]. They showed that breast cancer cells treated with serum collected from animal post exercise caused significant decrease in proliferation and increased apoptosis leading to abrogation of tumor growth [14]. Their later work has reported crosstalk between myokines and immune cells leading to the coining of the term ‘diseasome’ of physical activity.In the past few years, there has been an explosion in the number of cytokines secreted by contracting muscles (termed ‘myokinome’) that have been identified. Currently, there are more than 3000 myokines reported [15] with several of them having potential anticancer benefit. In an experimental model of colon carcinogenesis, a novel myokine SPARC has been shown to transduce the protective effects of exercise [16]. In addition, myokine irisin (FNDC5) has been shown to decrease breast cancer aggressiveness and also enhance chemotherapy [17]. Furthermore, a recent study, featured in the New England Journal of Medicine indicated that IL-6 had an antineoplastic benefit by targeting immune cells (NK cells) providing another putative mechanism of action [18]. In prostate cancer, there is speculation that myokines may interact with adipokines thereby potentially amplifying its effect. Additional studies using animal models of CRC and melanoma suggest that myokines manifest an anticancer effect in vivo [16]. Thus myokines represent a promising target for exercise induced antineoplastic effect. The mechanisms of exercise and cancer are likely pleotropic but may inform about potentially novel drug targets.The dissection of the precise myokine(s) involved through analysis of blood from animal or human studies is remarkably difficult given the challenges of analyzing the circulating proteome. Furthermore, many members of the myokinome have been reported to have antagonistic effects (e.g., some considered pro-neoplastic and others antineoplastic). Thus, unraveling the molecular interplay between myokines and identifying the potentially therapeutic ones necessitates a simplified system. Our laboratory has adapted the in vitro exercise platform (myotubules stimulated with C-Pace system) [19] and used it for the application of discovering specific myokines (individual or combination) which may have therapeutic effects. Our initial focus has been on synergism of myokines with chemotherapy in CRC [20]. Furthermore, we noted that myokines by itself exhibited some antineoplastic effect. This platform approach has implications for a variety of cancers along with non-neoplastic conditions which have been reported to benefit from exercise (obesity, atherosclerosis, diabetes and fatty liver, etc.). Importantly, given the paradigm for chemotherapy is combination (e.g., FOLFOX or FOLFIRI in CRC), the best approach may be a combination of myokines probably with conventional cytotoxic chemotherapy. Furthermore, since cancer is a heterogeneous disease, it is likely that myokines may be somewhat specific for cancer type or at least have similarities between different cancer types that have the same molecular drivers (e.g., Ras signaling).Therefore, these novel cell culture approaches may give a way to translate the epidemiological/biological insights of exercise into a ‘druggable’ antineoplastic target(s). Given the number of ‘biological’ agents in many fields of medicine including oncology, cardiovascular disease and immunology, among others, there is a clear precedence in clinical medicine. Moreover, this may provide a model to develop small molecule inhibitors/mimetic to these molecular targets. While cancer prevention is thought to be a more challenging target (given that you are treating healthy patients, the risk-benefit and cost-effective calculations become more stringent). However, the relegation of many cancers as a chronic disease underscores the clinical opportunities. Similarly, there may a combined therapeutic/preventive benefit in the increasingly important issues in cancer survivorship. Finally, there are also potential applications as biomarkers to optimize both the dosage and type of exercise (aerobic and resistance, etc.) to achieve the maximal therapeutic benefit. In this regard one could consider serum myokine(s) as a potential tool for risk stratification to allow precision medical approaches to screening strategies.ConclusionThere is emerging evidence that myokines may have significant antineoplastic benefits and may represent a major mechanism through which the salutary benefits of exercise are transduced. This may represent a new prototype for drug discovery for both neoplastic and benign diseases. The potential for putting ‘exercise-in-a-pill’ may represent a major new therapeutic vista.Financial & competing interests disclosureSupport in part by R33CA225323, R01CA200064 and R01CA183101. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Erdrich J, Zhang X, Giovannucci E, Willett W. Proportion of colon cancer attributable to lifestyle in a cohort of US women. Cancer Causes Control 26(9), 1271–1279 (2015).Crossref, Medline, Google Scholar2 Moore SC, Lee IM, Weiderpass E et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176(6), 816–825 (2016).Crossref, Medline, Google Scholar3 Ruiz-Casado A, Martin-Ruiz A, Perez LM, Provencio M, Fiuza-Luces C, Lucia A. Exercise and the hallmarks of cancer. Trends Cancer 3(6), 423–441 (2017).Crossref, Medline, CAS, Google Scholar4 Boyle T, Keegel T, Bull F, Heyworth J, Fritschi L. Physical activity and risks of proximal and distal colon cancers: a systematic review and meta-analysis. J. Natl Cancer Inst. 104(20), 1548–1561 (2012).Crossref, Medline, Google Scholar5 Mctiernan A, Yasui Y, Sorensen B et al. Effect of a 12-month exercise intervention on patterns of cellular proliferation in colonic crypts: a randomized controlled trial. Cancer Epidemiol. Biomarkers Prev. 15(9), 1588–1597 (2006).Crossref, Medline, CAS, Google Scholar6 Walter V, Jansen L, Knebel P, Chang-Claude J, Hoffmeister M, Brenner H. Physical activity and survival of colorectal cancer patients: population-based study from Germany. Int. J. Cancer 140(9), 1985–1997 (2017).Crossref, Medline, CAS, Google Scholar7 Meyerhardt JA, Heseltine D, Niedzwiecki D et al. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J. Clin. Oncol. 24(22), 3535–3541 (2006).Crossref, Medline, Google Scholar8 Park J, Kim JH, Lee HJ et al. The effects of physical activity and body fat mass on colorectal polyp recurrence in patients with previous colorectal cancer. Cancer Prev. Res. (Phila.) 10(8), 478–484 (2017).Crossref, Medline, Google Scholar9 Wu W, Guo F, Ye J et al. Pre- and post-diagnosis physical activity is associated with survival benefits of colorectal cancer patients: a systematic review and meta-analysis. Oncotarget 7(32), 52095–52103 (2016).Crossref, Medline, Google Scholar10 Brown JC, Troxel AB, Ky B et al. Dose-response effects of aerobic exercise among colon cancer survivors: a randomized Phase II trial. Clin. Colorectal Cancer doi:10.1016/j.clcc.2017.06.001 (2017) (Epub ahead of print).Crossref, Medline, Google Scholar11 Ruiz JR, Sui X, Lobelo F et al. Muscular strength and adiposity as predictors of adulthood cancer mortality in men. Cancer Epidemiol. Biomarkers Prev. 18(5), 1468–1476 (2009).Crossref, Medline, Google Scholar12 Delitto D, Judge SM, George TJ Jr et al. A clinically applicable muscular index predicts long-term survival in resectable pancreatic cancer. Surgery 161(4), 930–938 (2017).Crossref, Medline, Google Scholar13 Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiological Rev. 88(4), 1379–1406 (2008).Crossref, Medline, CAS, Google Scholar14 Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am. J. Physiol. Endocrinol. Metab. 301(3), e504–e510 (2011).Crossref, Medline, CAS, Google Scholar15 Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nature Rev. Drug Discov. 15(10), 719–729 (2016).Crossref, Medline, CAS, Google Scholar16 Aoi W, Naito Y, Takagi T et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62(6), 882–889 (2013).Crossref, Medline, CAS, Google Scholar17 Gannon NP, Vaughan RA, Garcia-Smith R, Bisoffi M, Trujillo KA. Effects of the exercise-inducible myokine irisin on malignant and non-malignant breast epithelial cell behavior in vitro. Int. J. Cancer 136(4), e197–e202 (2015).Crossref, Medline, CAS, Google Scholar18 Lucia A, Ramirez M. Muscling in on cancer. N. Engl. J. Med. 375(9), 892–894 (2016).Crossref, Medline, Google Scholar19 Evers-Van Gogh IJ, Alex S, Stienstra R, Brenkman AB, Kersten S, Kalkhoven E. Electric pulse stimulation of myotubes as an in vitro exercise model: cell-mediated and non-cell-mediated effects. Sci. Rep. 5, 10944 (2015).Crossref, Medline, Google Scholar20 Delacruz M, Ohm JT, Ledbetter SE et al. Towards identification of factors in exercise-induced colorectal cancer prevention: development of a novel cell culture model. Gastroenterology 150(4), S623 (2016).Crossref, Google ScholarFiguresReferencesRelatedDetailsCited ByEffect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced GIST26 August 2022 | BMC Gastroenterology, Vol. 22, No. 1Circadian rhythms and cancers: the intrinsic links and therapeutic potentials4 March 2022 | Journal of Hematology & Oncology, Vol. 15, No. 1Muscle-to-tumor crosstalk: The effect of exercise-induced myokine on cancer progressionBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, Vol. 1877, No. 5Exercise-induced myokines downregulates the ACE2 level in bronchial epithelial cells: Implications for SARS-CoV-2 prevention20 July 2022 | PLOS ONE, Vol. 17, No. 7Machine learning model for predicting excessive muscle loss during neoadjuvant chemoradiotherapy in oesophageal cancer17 June 2021 | Journal of Cachexia, Sarcopenia and Muscle, Vol. 12, No. 5Muscle-Derived Cytokines Reduce Growth, Viability and Migratory Activity of Pancreatic Cancer Cells29 July 2021 | Cancers, Vol. 13, No. 15Physical activity and cancer biology: navigating a pathophysiological maze and broadening therapeutic imagination30 November 2020 | The Journal of Physiology, Vol. 599, No. 5Feasibility of an Interactive Health Coaching Mobile App to Prevent Malnutrition and Muscle Loss in Esophageal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy: Prospective Pilot Study27 August 2021 | Journal of Medical Internet Research, Vol. 23, No. 8Prognostic Impact of Sarcopenia and Skeletal Muscle Loss During Neoadjuvant Chemoradiotherapy in Esophageal Cancer10 April 2020 | Cancers, Vol. 12, No. 4Activités physiques et cancers : des bénéfices prouvés pendant et après les traitementsBulletin du Cancer, Vol. 107, No. 4A healthy lifestyle pattern has a protective association with colorectal polyps30 July 2019 | European Journal of Clinical Nutrition, Vol. 74, No. 2Mechanisms of Exercise in Cancer Prevention, Treatment, and Survivorship5 May 2020Oncostatin M, a muscle-secreted myokine, recovers high-glucose-induced impairment of Akt phosphorylation by Fos induction in hippocampal neuron cellsNeuroReport, Vol. 30, No. 11 Vol. 14, No. 4 eToC Sign up Follow us on social media for the latest updates Metrics History Received 19 October 2017 Accepted 1 November 2017 Published online 10 January 2018 Published in print February 2018 Information© 2018 Future Medicine LtdKeywordsantineoplasticcolorectal cancerdiseasomeexerciseexercise-in-a-pillexogenous risk factorshallmarks of cancer in vitro exercise platformmyokinemyokinomeFinancial & competing interests disclosureSupport in part by R33CA225323, R01CA200064 and R01CA183101. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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