Exploring the role of adipokines in exercise-induced inhibition of tumor growth

Abstract

The integration of exercise prescriptions into cancer adjuvant therapy presents challenges stemming from the ambiguity surrounding the precise mechanism through which exercise intervention mitigates the risk of hepatocellular carcinoma (HCC) mortality and recurrence. Elucidation of this specific mechanism has substantial social and clinical implications. In this study, tumor-bearing mice engaged in voluntary wheel running exhibited a notable decrease in tumor growth, exceeding 30%. Microarray analysis revealed an upregulation of cytokine-related pathways as a potential explanation for this effect. The inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to enhance tumor cell proliferation, while the absence of GM-CSF resulted in a marked inhibition of tumor cell growth. The findings suggest that exercise-induced serum from mice can impede the proliferation of mouse tumor cells, with the adipokine chemerin inhibiting the growth factor GM-CSF. Additionally, exercise was found to stimulate chemerin secretion by brown adipose tissue. Chemerin suppression led to a reduction in the inhibition of tumor cell proliferation. The results of this study suggest that exercise may stimulate the release of adipokines from brown adipose tissue, transport them through the blood to the distant tumor microenvironment, and downregulate GM-CSF expression, alleviating tumor immunosuppression in the tumor microenvironment, thereby inhibiting at HCC progression. These findings provide a theoretical basis for incorporating exercise prescription into cancer treatment.

Keywords

Chemerin / GM-CSF / Hepatocellular carcinoma / Proliferation / Voluntary wheel running

References

[[1]] H. Sung, J. Ferlay, R.L. Siegel, et al.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin, 71 ( 2021), pp. 209-249, DOI: 10.3322/caac.21660

[[2]] J.M. Llovet, F. Castet, M. Heikenwalder, et al.. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol, 19 (3) ( 2022), pp. 151-172, DOI: 10.1038/s41571-021-00573-2

[[3]] S. Xia, Y. Pan, Y. Liang, J. Xu, X. Cai. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine, 51 ( 2020), Article 102610, DOI: 10.1016/j.ebiom.2019.102610

[[4]] M. Zamanian-Azodi, S. Khatoon Hajisayah, M. Razzaghi, M. Rezaei-Tavirani. Introducing physical exercise as a potential strategy in liver cancer prevention and development. Gastroenterol Hepatol Bed Bench., 14 ( 2021), pp. 317-322, DOI: 10.22037/ghfbb.v14i4.2250

[[5]] J.F. Meneses-Echávez, J.E. Correa-Bautista, E. González-Jiménez, et al.. The effect of exercise training on mediators of inflammation in breast cancer survivors: a systematic review with meta-analysis. Cancer Epidemiol Biomarkers Prev, 25 ( 2016), pp. 1009-1017, DOI: 10.1158/1055-9965.epi-15-1061

[[6]] J.F. Meneses-Echávez, E.G. Jiménez, J.S. Río-Valle, J.E. Correa-Bautista, M. Izquierdo, R. Ramírez-Vélez.The insulin-like growth factor system is modulated by exercise in breast cancer survivors: a systematic review and meta-analysis. BMC Cancer, 16 ( 2016), p. 682, DOI: 10.1186/s12885-016-2733-z

[[7]] J.F. Meneses-Echavez, I. Rodriguez-Prieto, M. Elkins, J. Martínez-Torres, L. Nguyen, J. Bidonde.Analysis of reporting completeness in exercise cancer trials: a systematic review. BMC Med Res Methodol, 19 ( 2019), p. 220, DOI: 10.1186/s12874-019-0871-0

[[8]] S. Koya, T. Kawaguchi, R. Hashida, et al.. Effects of in-hospital exercise on liver function, physical ability, and muscle mass during treatment of hepatoma in patients with chronic liver disease. Hepatol Res, 47 (3) ( 2017), pp. 22-34, DOI: 10.1111/hepr.12718

[[9]] J. Tsuchihashi, S. Koya, K. Hirota, et al.. Effects of In-hospital exercise on frailty in patients with hepatocellular carcinoma. Cancers, 13 ( 2021), p. 194, DOI: 10.3390/cancers13020194

[[10]] L. Pedersen, M. Idorn, Gitte H. Olofsson, et al.. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabol, 23 ( 2016), pp. 554-562, DOI: 10.1016/j.cmet.2016.01.011

[[11]] H. Jee, E. Park, K. Hur, M. Kang, Y. Kim. High-intensity aerobic exercise suppresses cancer growth by regulating skeletal muscle-derived oncogenes and tumor suppressors. Front Mol Biosci, 9 ( 2022), Article 818470, DOI: 10.3389/fmolb.2022.818470

[[12]] U. Saran, M. Guarino, S. Rodríguez, et al.. Anti-tumoral effects of exercise on hepatocellular carcinoma growth. Hepatol Commun, 2 ( 2018), pp. 607-620, DOI: 10.1002/hep4.1159

[[13]] A. Budhu, S. Roessler, X. Zhao, et al.. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology, 144 ( 2013), pp. 1066-1075. e1061, DOI: 10.1053/j.gastro.2013.01.054

[[14]] L. Zhao, W. Yang, X. Yang, et al.. Chemerin suppresses murine allergic asthma by inhibiting CCL 2 production and subsequent airway recruitment of inflammatory dendritic cells. Allergy, 69 ( 2014), pp. 763-774, DOI: 10.1111/all.12408

[[15]] T.F. Fischer, A.G. Beck-Sickinger. Chemerin - exploring a versatile adipokine. Biol Chem, 403 ( 2022), pp. 625-642, DOI: 10.1515/hsz-2021-0409

[[16]] Y. Gepner, I. Shelef, O. Komy, et al.. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J Hepatol, 71 (2) ( 2019), pp. 379-388, DOI: 10.1016/j.jhep.2019.04.013

[[17]] S. Kolahdouzi, M. Baghadam, F.A. Kani-Golzar, et al.. Progressive circuit resistance training improves inflammatory biomarkers and insulin resistance in obese men. Physiol Behav, 205 ( 2019), pp. 15-21, DOI: 10.1016/j.physbeh.2018.11.033

[[18]] T. Stefanov, M. Blüher, A. Vekova, et al.. Circulating chemerin decreases in response to a combined strength and endurance training. Endocrine, 45 (3) ( 2014), pp. 382-391, DOI: 10.1007/s12020-013-0003-2

[[19]] B. Skrzep-Poloczek, M. Idzik, K. Michalczyk, et al.. A 21-day individual rehabilitation exercise training program changes irisin, chemerin, and BDNF levels in patients after hip or knee replacement surgery. J Clin Med, 12 (15) ( 2023), p. 4881, DOI: 10.3390/jcm12154881

[[20]] A. Czajkowska, J. Ambroszkiewicz, A. Mróz, K. Witek, D. Nowicki, Ł. Małek.The effect of the ultra-marathon run at a distance of 100 kilometers on the concentration of selected adipokines in adult men. Int J Environ Res Publ Health, 17 (12) ( 2020), p. 4289, DOI: 10.3390/ijerph17124289

[[21]] N. Ouerghi, M.K.B. Fradj, M. Khammassi, M. Feki, N. Kaabachi, A. Bouassida. Plasma chemerin in young untrained men: association with cardio-metabolic traits and physical performance, and response to intensive interval training. Neuroendocrinol Lett, 38 (1) ( 2017), pp. 59-66

[[22]] J.W. Lloyd, K.M. Zerfass, E.M. Heckstall, K.A. Evans. Diet-induced increases in chemerin are attenuated by exercise and mediate the effect of diet on insulin and HOMA-IR. Ther Adv Endocrinol Metab, 6 (5) ( 2015), pp. 189-198, DOI: 10.1177/2042018815589088

[[23]] C. Ben Dhaou, K. Mandi, M. Frye, et al.. Chemerin regulates normal angiogenesis and hypoxia-driven neovascularization. Angiogenesis, 25 ( 2022), pp. 159-179, DOI: 10.1007/s10456-021-09818-1

[[24]] O. Treeck, C. Buechler,O. Ortmann. Chemerin and cancer. Int J Mol Sci, 20 ( 2019), p. 3750, DOI: 10.3390/ijms20153750

[[25]] J.J. Li, H.K. Yin, D.X. Guan, et al.. Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis. Br J Cancer, 118 ( 2018), pp. 1337-1348, DOI: 10.1038/s41416-018-0077-y

[[26]] K. Imai, K. Takai, T. Hanai, et al.. Impact of serum chemerin levels on liver functional reserves and platelet counts in patients with hepatocellular carcinoma. Int J Mol Sci, 15 ( 2014), pp. 11294-11306, DOI: 10.3390/ijms150711294

[[27]] M. Li, P. Sun, K. Dong, et al.. Chemerin reverses the malignant phenotype and induces differentiation of human hepatoma SMMC7721 cells. Arch Pharm Res (Seoul), 44 (2) ( 2021), pp. 194-204, DOI: 10.1007/s12272-021-01311-z

[[28]] L. Zhao, L.L. Leung, J. Morser. Chemerin forms: their generation and activity. Biomedicines, 10 ( 2022), p. 2018, DOI: 10.3390/biomedicines10082018

[[29]] K.B. Goralski, A.E. Jackson, B.T. McKeown, C.J. Sinal.More than an adipokine: the complex roles of chemerin signaling in cancer. Int J Mol Sci, 20 ( 2019), p. 4778, DOI: 10.3390/ijms20194778

[[30]] K.S. Pedersen, F. Gatto, B. Zerahn, et al.. Exercise-mediated lowering of glutamine availability suppresses tumor growth and attenuates muscle wasting. iScience, 23 (4) ( 2020), Article 100978, DOI: 10.1016/j.isci.2020.100978

[[31]] R. Esteban-Fabró, C.E. Willoughby, M. Piqué-Gili, et al.. Cabozantinib enhances Anti-PD 1 activity and elicits a neutrophil-based immune response in hepatocellular carcinoma. Clin Cancer Res, 28 (11) ( 2022), pp. 2449-2460, DOI: 10.1158/1078-0432.CCR-21-2517

[[32]] B. Zhou, J. Yan, L. Guo, et al.. Hepatoma cell-intrinsic TLR9 activation induces immune escape through PD-L 1 upregulation in hepatocellular carcinoma. Theranostics, 10 (14) ( 2020), pp. 6530-6543, DOI: 10.7150/thno.44417

[[33]] Y.C. Ye, J.L. Zhao, Y.T. Lu, et al.. NOTCH signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res, 79 (16) ( 2019), pp. 4160-4172, DOI: 10.1158/0008-5472.CAN-18-1691

[[34]] C. Dopazo, K. Søreide, E. Rangelova, et al.. Hepatocellular carcinoma. Eur J Surg Oncol, 50 (1) ( 2024), Article 107313, DOI: 10.1016/j.ejso.2023.107313

[[35]] Y. Wang, B. Deng. Hepatocellular carcinoma:molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev, 42 (3) ( 2023), pp. 629-652, DOI: 10.1007/s10555-023-10084-4

[[36]] S. Tao, S. Liang, T. Zeng, D. Yin. Epigenetic modification-related mechanisms of hepatocellular carcinoma resistance to immune checkpoint inhibition. Front Immunol, 13 ( 2023), Article 1043667, DOI: 10.3389/fimmu.2022.1043667

[[37]] L. Fehrenbacher, A. Spira, M. Ballinger, et al.. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 387 (10030) ( 2016), pp. 1837-1846, DOI: 10.1016/S0140-6736(16)00587-0

[[38]] J.M. Llovet, R.K. Kelley, A. Villanueva, et al.. Hepatocellular carcinoma. Nat Rev Dis Prim, 7 (1) ( 2021), p. 6, DOI: 10.1038/s41572-020-00240-3

[[39]] A. Perrier, A. Didelot, P. Laurent-Puig, H. Blons, S. Garinet. Epigenetic mechanisms of resistance to immune checkpoint inhibitors. Biomolecules, 10 (7) ( 2020), p. 1061, DOI: 10.3390/biom10071061

[[40]] T. Zhao, B.-J. Guo, C.-L. Xiao, et al.. Aerobic exercise suppresses hepatocellular carcinoma by downregulating dynamin-related protein 1 through PI3K/AKT pathway. J Integr Med, 19 (5) ( 2021), pp. 418-427, DOI: 10.1016/j.joim.2021.08.003

[[41]] A. Arfianti, S. Pok, V. Barn, et al.. Exercise retards hepatocarcinogenesis in obese mice independently of weight control. J Hepatol, 73 (1) ( 2020), pp. 140-148, DOI: 10.1016/j.jhep.2020.02.006

[[42]] A. Sitlinger, D.M. Brander, D.B. Bartlett. Impact of exercise on the immune system and outcomes in hematologic malignancies. Blood Adv, 4 (8) ( 2020), pp. 1801-1811, DOI: 10.1182/bloodadvances.2019001317

[[43]] G.J. Koelwyn, E. Wennerberg, S. Demaria, L.W. Jones. Exercise in regulation of inflammation-immune axis function in cancer initiation and progression. Oncology, 29 (12) ( 2015), pp. 908-922

[[44]] M. Idorn,Straten P. Thor. Exercise and Cancer: from "healthy" to "therapeutic"?. Cancer Immun, 66 (5) ( 2017), pp. 667-671, DOI: 10.1007/s00262-017-1985-z

[[45]] R. Hashida, H. Matsuse, T. Kawaguchi, et al.. Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703,and Fractalkine/CX3CL 1 expressions in subjects with No exercise habits: a preliminary study. Hepatol Res, 51 (7) ( 2021), pp. 823-833, DOI: 10.1111/hepr.13670

[[46]] I.S. Hong.Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. Exp Mol Med, 48 (7) ( 2016), p. e242, DOI: 10.1038/emm.2016.64

[[47]] A. Kumar, A. Taghi Khani, A. Sanchez Ortiz, S. Swaminathan. GM-CSF: a double-edged sword in cancer immunotherapy. Front Immunol, 13 ( 2022), Article 901277, DOI: 10.3389/fimmu.2022.901277

[[48]] O. Treeck, C. Buechler,O. Ortmann. Chemerin and cancer. Int J Mol Sci, 20 (15) ( 2019), p. 3750, DOI: 10.3390/ijms20153750

[[49]] T. Sledzinski, J. Korczynska, A. Hallmann, et al.. The increase of serum chemerin concentration is mainly associated with the increase of body mass index in obese, non-diabetic subjects. J Endocrinol Invest, 36 (6) ( 2013), pp. 428-434, DOI: 10.3275/8770

[[50]] J. Li, Y. Lu, N. Li, et al.. Chemerin: a potential regulator of inflammation and metabolism for chronic obstructive pulmonary disease and pulmonary rehabilitation. BioMed Res Int, 2020 ( 2020), Article 4574509, DOI: 10.1155/2020/4574509

[[51]] Y. Lin, X. Yang, W. Liu, et al.. Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation. Oncogene, 36 (25) ( 2017), pp. 3599-3608, DOI: 10.1038/onc.2016.516

[[52]] W. Yu, Q. Lei, L. Yang, et al.. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol, 14 (1) ( 2021), p. 187, DOI: 10.1186/s13045-021-01200-4

[[53]] K.C. Corn, M.A. Windham, M. Rafat. Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res, 80 ( 2020), pp. 10-55, DOI: 10.1016/j.plipres.2020.101055

[[54]] M. Alannan, H. Fayyad-Kazan, V. Trézéguet, A. Merched. Targeting lipid metabolism in liver cancer. Biochemistry, 59 (41) ( 2020), pp. 3951-3964, DOI: 10.1021/acs.biochem.0c00477