Exercise Training and Cytokines in Breast Cancer Survivors

Abstract

The purpose of this randomized controlled trial was to determine the effects of an 8-week (aerobic+strength) exercise training program (3 sessions/week) on the circulating cytokine levels of breast cancer survivors. We randomly allocated 16 female survivors of breast cancer (mean±SD age: 50±5 years) to an intervention or usual care (control) group (N=8 in each group). The intervention group followed an 8-week exercise program consisting of 3 sessions/week (session duration: 90 min). We measured the levels of the following cytokines before and after the intervention: beta-NGF, CTACK, eotaxin, FGF basic, G-CSF, gmCSFα, HGF, ICAM1, IFNα2, IFNγ, IL1α, IL1ß, IL1ra, IL2, IL2ra, IL3, IL4, IL6, IL7, IL8, IL9, IL10, IL12, IL13, IL15, IL16, IL17, IL18, IP10, LIF, MCS-F, MIP1α, MIP1β, MIF, MCP1, MCP3, MIG, PDGF bb, SCF, SCGFβ, SDF1α, TRAIL, TNFα, TNFβ, VCAM1, and VEGF. We only observed a significant interaction (group*time) effect for CTACK (P=0.016), with mean values remaining stable in the intervention group but increasing over time in controls. The intervention program did not induce a significant decrease in the main breast cancer-related cytokines such as IL6 and IL8. A combined (aerobic+strength) 8-week exercise training intervention did not induce major changes in the basal cytokine levels of breast cancer survivors.

Key words

physical activity - inflammation - tumour - interleukins

References

• 1 Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, Paraskevaidis J, Koniavitou K, Coats AJ, Kremastinos DT. Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure.  J Am Coll Cardiol. 2002;  39 653-663
• 2 Bacurau RF, Belmonte MA, Seelaender MC, Costa Rosa LF. Effect of a moderate intensity exercise training protocol on the metabolism of macrophages and lymphocytes of tumour-bearing rats.  Cell Biochem Funct. 2000;  18 249-258
• 3 Bach JP, Deuster O, Balzer-Geldsetzer M, Meyer B, Dodel R, Bacher M. The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors.  Cancer. 2009;  115 2031-2040
• 4 Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, Vermeulen PB, Dirix LY. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival.  Clin Cancer Res. 2004;  10 7157-7162
• 5 Borish LC, Steinke JW. 2. Cytokines and chemokines.  J Allergy Clin Immunol. 2003;  111 S460-S475
• 6 Bruunsgaard H. Physical activity and modulation of systemic low-level inflammation.  J Leukoc Biol. 2005;  78 819-835
• 7 Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity.  Nat Rev Immunol. 2003;  3 791-800
• 8 Conraads VM, Beckers P, Bosmans J, De Clerck LS, Stevens WJ, Vrints CJ, Brutsaert DL. Combined endurance/resistance training reduces plasma TNF-alpha receptor levels in patients with chronic heart failure and coronary artery disease.  Eur Heart J. 2002;  23 1854-1860
• 9 Coussens LM, Werb Z. Inflammation and cancer.  Nature. 2002;  420 860-867
• 10 Demarzo MM, Martins LV, Fernandes CR, Herrero FA, Perez SE, Turatti A, Garcia SB. Exercise reduces inflammation and cell proliferation in rat colon carcinogenesis.  Med Sci Sports Exerc. 2008;  40 618-621
• 11 DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression.  Breast Cancer Res. 2007;  9 212
• 12 Gamero AM, Ussery D, Reintgen DS, Puleo CA, Djeu JY. Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism.  Cancer Res. 1995;  55 4988-4994
• 13 Goldhammer E, Tanchilevitch A, Maor I, Beniamini Y, Rosenschein U, Sagiv M. Exercise training modulates cytokines activity in coronary heart disease patients.  Int J Cardiol. 2005;  100 93-99
• 14 Harriss DJ, Atkinson G. International Journal of Sports Medicine – Ethical Standards in Sport and Exercise Science Research.  Int J Sports Med. 2009;  30 701-702
• 15 Herrero F, San Juan AF, Fleck SJ, Balmer J, Perez M, Canete S, Earnest CP, Foster C, Lucia A. Combined aerobic and resistance training in breast cancer survivors: A randomized, controlled pilot trial.  Int J Sports Med. 2006;  27 573-580
• 16 Holm S. A simple sequentially rejective multiple test procedure.  Scand J Statist. 1979;  6 65-70
• 17 Homey B, Alenius H, Muller A, Soto H, Bowman EP, Yuan W, McEvoy L, Lauerma AI, Assmann T, Bunemann E, Lehto M, Wolff H, Yen D, Marxhausen H, To W, Sedgwick J, Ruzicka T, Lehmann P, Zlotnik A. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.  Nat Med. 2002;  8 157-165
• 18 Irwin ML. Physical activity interventions for cancer survivors.  Br J Sports Med. 2009;  43 32-38
• 19 Jiang XP, Yang DC, Elliott RL, Head JF. Reduction in serum IL-6 after vaccination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status.  Cytokine. 2000;  12 458-465
• 20 Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss.  J Nutr Biochem. 2008;  19 371-375
• 21 Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ. Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients.  Rocz Akad Med Bialymst. 2003;  48 82-84
• 22 Kraynyak KA, Kutzler MA, Cisper NJ, Khan AS, Draghia-Akli R, Sardesal NY, Lewis MG, Yan J, Weiner DB. Systemic immunization with CCL27/CTACK modulates immune responses at mucosal sites in mice and macaques.  Vaccine. 2010;  28 1942-1951
• 23 Lira FS, Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, Batista Jr ML, Seelaender M. Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise.  Cell Biochem Funct. 2009;  27 71-75
• 24 Lucia A, Earnest C, Perez M. Cancer-related fatigue: can exercise physiology assist oncologists?.  Lancet Oncol. 2003;  4 616-625
• 25 Mitchell RA, Metz CN, Peng T, Bucala R. Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action.  J Biol Chem. 1999;  274 18100-18106
• 26 Munger W, DeJoy SQ, Jeyaseelan Sr R, Torley LW, Grabstein KH, Eisenmann J, Paxton R, Cox T, Wick MM, Kerwar SS. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2.  Cell Immunol. 1995;  165 289-293
• 27 Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, Yamashita H, Fukuda M, Mizumoto T, Hamamoto R. An analysis of serum interleukin-6 levels to predict benefits of medroxyprogesterone acetate in advanced or recurrent breast cancer.  Oncology. 2000;  59 166-173
• 28 Oberbach A, Tonjes A, Kloting N, Fasshauer M, Kratzsch J, Busse MW, Paschke R, Stumvoll M, Bluher M. Effect of a 4 week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance.  Eur J Endocrinol. 2006;  154 577-585
• 29 Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise.  J Appl Physiol. 2005;  98 1154-1162
• 30 Polak J, Klimcakova E, Moro C, Viguerie N, Berlan M, Hejnova J, Richterova B, Kraus I, Langin D, Stich V. Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor alpha in obese women.  Metabolism. 2006;  55 1375-1381
• 31 Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E, Huget P, Dirix LY. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer.  Int J Cancer. 2003;  103 642-646
• 32 Schmitz KH, Ahmed RL, Troxel A, Cheville A, Smith R, Lewis-Grant L, Bryan CJ, Williams-Smith CT, Greene QP. Weight lifting in women with breast-cancer-related lymphedema.  N Engl J Med. 2009;  361 664-673
• 33 Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer.  Nat Rev Cancer. 2008;  8 887-899
• 34 Timmons BW, Hamadeh MJ, Tarnopolsky MA. Two methods for determining plasma IL-6 in humans at rest and following exercise.  Eur J Appl Physiol. 2009;  105 13-18
• 35 Verjans E, Noetzel E, Bektas N, Schutz AK, Lue H, Lennartz B, Hartmann A, Dahl E, Bernhagen J. Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer.  BMC Cancer. 2009;  9 230
• 36 Yu YL, Wei CW, Chen YL, Chen MH, Yiang GT. Immunotherapy of breast cancer by single delivery with rAAV2-mediated interleukin-15 expression.  Int J Oncol. 2010;  36 365-370

1 A. M. Gómez and C. Martínez contributed equally to this paper and A. Lucia and A. Ramírez share senior authorship.

Correspondence