The effects of 4-week aerobic exercise on the levels of CCL2, CCL5, and their respective receptors in female BALB/C mice suffering from breast cancer

Esmailiyan, Mehrnoosh; Kargarfard, Mehdi; Esfarjani, Fahimeh; Vaseghi, Golnaz; Javanmard, Shaghayegh Haghjooy; Amerizadeh, Atefeh

The effects of 4-week aerobic exercise on the levels of CCL2, CCL5, and their respective receptors in female BALB/C mice suffering from breast cancer

Authors

¹ Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran

² Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Science, Isfahan, Iran

³ Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: The studies reported that chemokines Chemokine (C-C motif) ligand 2 (CCL2) and Chemokine (C-C motif) ligand 5 (CCL5) have tumor-promoting roles in breast cancer (BC). The aim of the present study was to evaluate the effect of 4 weeks of continuous aerobic exercise (AE) on chemokines CCL2 and CCL5 and their relative receptors in animal model of human BC.
Materials and Methods: BALB/c mice were divided randomly into four groups included cancer control (CC) and three other groups. The total duration of the experiment was 14 weeks, including 2 weeks of familiarization of mice with treadmills and three of 4-week periods of experiment. Tumor inoculation and formation were performed in the second 4-week period. Group 1 received AE in the first 4-week, Group 2 received AE in the second 4-week and Group 3 in the third 4-week.
Results: The CCL2 was reduced significantly in Groups 1, 2, and 3 compared to control (F_3,12 = 4705, P = 0.0001). In terms of CCL5, a significant decrease was seen only between Group 3 and control. Western blot results showed a significant reduction in C-C chemokine receptor Type 2 (CCR2) between Group 1 versus CC and Group 2 versus CC (F_3,20 = 1.812, P = 0.004). In terms of C-C chemokine receptor Type 5 (CCR5) a significant decrease was observed between Group 2 versus control and Group 3 versus control (F_3,20 = 273.3, P = 0.042), (P = 0.004).
Conclusion: It can be concluded that 4-week AE significantly reduces the chemokines CCL2 and CCL5 and their respective receptors levels CCR5 and CCR2 in different stages, and it may have an inhibitory effect on tumor growth.

Keywords

References

1.	Available from: https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/. [Last accessed on 2020 Oct 11].
2.	Spei ME, Samoli E, Bravi F, La Vecchia C, Bamia C, Benetou V. Physical activity in breast cancer survivors: A systematic review and meta-analysis on overall and breast cancer survival. Breast 2019;44:144-52.
3.	Jayedi A, Emadi A, Khan TA, Abdolshahi A, Shab-Bidar S. Dietary fiber and survival in women with breast cancer: A dose-response meta-analysis of prospective cohort studies. Nutr Cancer 2021;73:1570-80.
4.	Lee J. A meta-analysis of the association between physical activity and breast cancer mortality. Cancer Nurs 2019;42:271-85.
5.	de Boer MC, Wörner EA, Verlaan D, van Leeuwen PA. The mechanisms and effects of physical activity on breast cancer. Clin Breast Cancer 2017;17:272-8.
6.	Patel JG, Bhise AR. Effect of aerobic exercise on cancer-related fatigue. Indian J Palliat Care 2017;23:355-61. [PUBMED] [Full text]
7.	Jones LW, Viglianti BL, Tashjian JA, Kothadia SM, Keir ST, Freedland SJ, et al. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol (1985) 2010;108:343-8.
8.	Ashcraft KA, Peace RM, Betof AS, Dewhirst MW, Jones LW. Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: A critical systematic review of in vivo preclinical data. Cancer Res 2016;76:4032-50.
9.	Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett 2008;267:271-85.
10.	Dal Bo M, De Mattia E, Baboci L, Mezzalira S, Cecchin E, Assaraf YG, et al. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020;51:100702.
11.	Murphy EA, Davis JM, Barrilleaux TL, McClellan JL, Steiner JL, Carmichael MD, et al. Benefits of exercise training on breast cancer progression and inflammation in C3 (1) SV40Tag mice. Cytokine 2011;55:274-9.
12.	Powell AG, Parkinson D, Patel N, Chan D, Christian A, Lewis WG. Prognostic significance of serum inflammatory markers in gastric cancer. J Gastrointest Surg 2018;22:595-605.
13.	Svensson S, Abrahamsson A, Rodriguez GV, Olsson AK, Jensen L, Cao Y, et al. CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clin Cancer Res 2015;21:3794-805.
14.	Shalamzari SA, Agha-Alinejad H, Alizadeh S, Shahbazi S, Khatib ZK, Kazemi A, et al. The effect of exercise training on the level of tissue IL-6 and vascular endothelial growth factor in breast cancer bearing mice. Iran J Basic Med Sci 2014;17:231-58.
15.	Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017;17:559-72.
16.	Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem 2012;287:36593-608.
17.	Chiu HY, Sun KH, Chen SY, Wang HH, Lee MY, Tsou YC, et al. Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells. Cytokine 2012;59:423-32.
18.	Soria G, Ofri-Shahak M, Haas I, Yaal-Hahoshen N, Leider-Trejo L, Leibovich-Rivkin T, et al. Inflammatory mediators in breast cancer: Coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition. BMC Cancer 2011;11:130.
19.	Chen W, Qin Y, Liu S. Cytokines, breast cancer stem cells (BCSCs) and chemoresistance. Clin Transl Med 2018;7:27.
20.	Hembruff SL, Jokar I, Yang L, Cheng N. Loss of transforming growth factor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promote mammary tumor progression through macrophage-dependent and -independent mechanisms. Neoplasia 2010;12:425-33.
21.	Masuda T, Noda M, Kogawa T, Kitagawa D, Hayashi N, Jomori T, et al. Phase I dose-escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer. Cancer Sci 2020;111:924-31.

Advanced Biomedical Research