Download PDF
Int J Sports Med 2021; 42(14): 1237-1249
DOI: 10.1055/a-1533-1876
Review

The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis

Mário Esteves
1   Laboratory of Biochemistry and Experimental Morphology, CIAFEL, Porto, Portugal
2   Department of Physical Medicine and Rehabilitation, Teaching Hospital of the Fernando Pessoa University, Gondomar, Portugal
,
Mariana P. Monteiro
3   Department of Anatomy, Universidade do Porto Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
,
Jose Alberto Duarte
1   Laboratory of Biochemistry and Experimental Morphology, CIAFEL, Porto, Portugal
4   TOXRUN - Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Gandra, Portugal
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

A wealth of evidence supports an association between physical exercise, decreased tumor growth rate, and reduced risk of cancer mortality. In this context, the tumor vascular microenvironment may play a key role in modulating tumor biologic behavior. The present systematic review and meta-analysis aimed to summarize the evidence regarding the effects of physical exercise on tumor vasculature in pre-clinical studies. We performed a computerized research on the PubMed, Scopus, and EBSCO databases to identify pre-clinical studies that evaluated the effect of physical exercise on tumor vascular outcomes. Mean differences were calculated through a random effects model. The present systematic review included 13 studies involving 373 animals. From these, 11 studies evaluated chronic intratumoral vascular adaptations and 2 studies assessed the acute intratumoral vascular adaptations to physical exercise. The chronic intratumoral vascular adaptations resulted in higher tumor microvessel density in 4 studies, increased tumor perfusion in 2 studies, and reduced intratumoral hypoxia in 3 studies. Quantitatively, regular physical exercise induced an increased tumor vascularization of 2.13 [1.07, 3.20] (p<0.0001). The acute intratumoral vascular adaptations included increased vascular conductance and reduced vascular resistance, which improved tumor perfusion and attenuated intratumoral hypoxia. In pre-clinical studies, physical exercise seems to improve tumor vascularization.

Key words

cancer - physical activity - vascularization - perfusion - hypoxia - angiogenesis


Publication History

Received: 19 March 2021

Accepted: 08 June 2021

Article published online:
02 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

Comment to this article:

Reply to the Letter to the Editor from Dr. Seet-Lee and ColleaguesInt J Sports Med 2022; 43(03): 288-288
DOI: 10.1055/a-1754-3377

Comment to this article:

Letter to the Editor on: “The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-Analysis.”Int J Sports Med 2022; 43(03): 286-287
DOI: 10.1055/a-1754-3323

 

  • References

  • 1 Bray F, Ferlay J, Soerjomataram I. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424 doi:10.3322/caac.21492
    CrossrefPubMedGoogle Scholar
  • 2 Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front Immunol 2020; 11: 940 doi:10.3389/fimmu.2020.00940
    Google Scholar
  • 3 Esteves M, Monteiro MP, Duarte JA. Role of regular physical exercise in tumor vasculature: favorable modulator of tumor milieu. Int J Sports Med 2021; 42: 389-406 doi:10.1055/a-1308-3476
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Jing X, Yang F, Shao C. et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer 2019; 18: 157 doi:10.1186/s12943-019-1089-9
    CrossrefPubMedGoogle Scholar
  • 5 Petrova V, Annicchiarico-Petruzzelli M, Melino G. et al. The hypoxic tumour microenvironment. Oncogenesis 2018; 7: 10 doi:10.1038/s41389-017-0011-9
    CrossrefPubMedGoogle Scholar
  • 6 Siemann DW, Horsman MR. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol Ther 2015; 153: 107-124 doi:10.1016/j.pharmthera.2015.06.006
    CrossrefPubMedGoogle Scholar
  • 7 Jo Y, Choi N, Kim K. et al. Chemoresistance of cancer cells: Requirements of tumor microenvironment-mimicking in vitro models in anti-cancer drug development. Theranostics 2018; 8: 5259-5275 doi:10.7150/thno.29098
    CrossrefPubMedGoogle Scholar
  • 8 Noman MZ, Hasmim M, Messai Y. et al. Hypoxia: A key player in antitumor immune response. A review in the theme: Cellular responses to hypoxia. Am J Physiol Cell Physiol 2015; 309: C569-C579 doi:10.1152/ajpcell.00207.2015
    CrossrefPubMedGoogle Scholar
  • 9 Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu Rev Physiol 2019; 81: 505-534 doi:10.1146/annurev-physiol-020518-114700
    CrossrefPubMedGoogle Scholar
  • 10 Goel S, Wong AH, Jain RK. Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2012; 2: a006486 doi:10.1101/cshperspect.a006486
    CrossrefPubMedGoogle Scholar
  • 11 Mittal K, Ebos J, Rini B. Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. Semin Oncol 2014; 41: 235-251 doi:10.1053/j.seminoncol.2014.02.007
    CrossrefPubMedGoogle Scholar
  • 12 Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 2009; 15: 5020-5025 doi:10.1158/1078-0432.CCR-09-0095
    CrossrefPubMedGoogle Scholar
  • 13 Paez-Ribes M, Allen E, Hudock J. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15: 220-231 doi:10.1016/j.ccr.2009.01.027
    CrossrefPubMedGoogle Scholar
  • 14 Multhoff G, Radons J, Vaupel P. Critical role of aberrant angiogenesis in the development of tumor hypoxia and associated radioresistance. Cancers (Basel) 2014; 6: 813-828 doi:10.3390/cancers6020813
    CrossrefPubMedGoogle Scholar
  • 15 Moserle L, Jimenez-Valerio G, Casanovas O. Antiangiogenic therapies: Going beyond their limits. Cancer Discov 2014; 4: 31-41 doi:10.1158/2159-8290.CD-13-0199
    CrossrefPubMedGoogle Scholar
  • 16 Philip PA. Targeting angiogenesis in pancreatic cancer. Lancet 2008; 371: 2062-2064 doi:10.1016/S0140-6736(08)60770-9
    CrossrefPubMedGoogle Scholar
  • 17 Betrian S, Bergeron C, Blay JY. et al. Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: Data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC's). Clin Sarcoma Res 2017; 7: 10 doi:10.1186/s13569-017-0076-4
    CrossrefPubMedGoogle Scholar
  • 18 McTiernan A, Friedenreich CM, Katzmarzyk PT. et al. Physical activity in cancer prevention and survival: A systematic review. Med Sci Sports Exerc 2019; 51: 1252-1261 doi:10.1249/MSS.0000000000001937
    CrossrefPubMedGoogle Scholar
  • 19 Rezende LFM, Sa TH, Markozannes G. et al. Physical activity and cancer: an umbrella review of the literature including 22 major anatomical sites and 770 000 cancer cases. Br J Sports Med 2018; 52: 826-833 doi:10.1136/bjsports-2017-098391
    CrossrefPubMedGoogle Scholar
  • 20 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 2016; 176: 816-825 doi:10.1001/jamainternmed.2016.1548
    CrossrefPubMedGoogle Scholar
  • 21 Patel AV, Friedenreich CM, Moore SC. et al. American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Med Sci Sports Exerc 2019; 51: 2391-2402 doi:10.1249/MSS.0000000000002117
    CrossrefPubMedGoogle Scholar
  • 22 Eschke RK, Lampit A, Schenk A. et al. Impact of physical exercise on growth and progression of cancer in rodents – a systematic review and meta-analysis. Front Oncol 2019; 9: 35 doi:10.3389/fonc.2019.00035
    Google Scholar
  • 23 Esteves M, Silva C, Pereira SS. et al. Regular voluntary running inhibits androgen-independent prostate cancer growth in mice. J Phys Act Health 2021; DOI: 10.1123/jpah.2020-0761.
    CrossrefPubMedGoogle Scholar
  • 24 Hojman P. Exercise protects from cancer through regulation of immune function and inflammation. Biochem Soc Trans 2017; 45: 905-911 doi:10.1042/BST20160466
    CrossrefPubMedGoogle Scholar
  • 25 Hojman P, Gehl J, Christensen JF. et al. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab 2018; 27: 10-21 doi:10.1016/j.cmet.2017.09.015
    CrossrefPubMedGoogle Scholar
  • 26 Kesting S, Weeber P, Schonfelder M. et al. Exercise as a potential intervention to modulate cancer outcomes in children and adults?. Front Oncol 2020; 10: 196 doi:10.3389/fonc.2020.00196
    CrossrefPubMedGoogle Scholar
  • 27 Ashcraft KA, Warner AB, Jones LW. et al. Exercise as adjunct therapy in cancer. Semin Radiat Oncol 2019; 29: 16-24 doi:10.1016/j.semradonc.2018.10.001
    CrossrefPubMedGoogle Scholar
  • 28 Koelwyn GJ, Quail DF, Zhang X. et al. Exercise-dependent regulation of the tumour microenvironment. Nat Rev Cancer 2017; 17: 620-632 doi:10.1038/nrc.2017.78
    CrossrefPubMedGoogle Scholar
  • 29 Isanejad A, Alizadeh AM, Amani Shalamzari S. et al. MicroRNA-206, let-7a and microRNA-21 pathways involved in the anti-angiogenesis effects of the interval exercise training and hormone therapy in breast cancer. Life Sci 2016; 151: 30-40 doi:10.1016/j.lfs.2016.02.090
    CrossrefPubMedGoogle Scholar
  • 30 Buss LA, Ang AD, Hock B. et al. Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice. PLoS One 2020; 15: e0229290 doi:10.1371/journal.pone.0229290
    CrossrefPubMedGoogle Scholar
  • 31 Dufresne S, Gueritat J, Chiavassa S. et al. Exercise training improves radiotherapy efficiency in a murine model of prostate cancer. FASEB J 2020; 34: 4984-4996 doi:10.1096/fj.201901728R
    CrossrefPubMedGoogle Scholar
  • 32 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097 doi:10.1371/journal.pmed.1000097
    CrossrefPubMedGoogle Scholar
  • 33 Hooijmans CR, Rovers MM, de Vries RB. et al. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 43 doi:10.1186/1471-2288-14-43
    CrossrefPubMedGoogle Scholar
  • 34 Schmidt FL, Oh IS, Hayes TL. Fixed- versus random-effects models in meta-analysis: model properties and an empirical comparison of differences in results. Br J Math Stat Psychol 2009; 62: 97-128 doi:10.1348/000711007X255327
    CrossrefPubMedGoogle Scholar
  • 35 Macleod MR, O'Collins T, Howells DW. et al. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004; 35: 1203-1208 doi:10.1161/01.STR.0000125719.25853.20
    CrossrefPubMedGoogle Scholar
  • 36 Florez Bedoya CA, Cardoso ACF, Parker N. et al. Exercise during preoperative therapy increases tumor vascularity in pancreatic tumor patients. Sci Rep 2019; 9: 13966 doi:10.1038/s41598-019-49582-3
    Google Scholar
  • 37 Jones LW, Antonelli J, Masko EM. et al. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer. J Appl Physiol (1985) 2012; 113: 263-272 doi:10.1152/japplphysiol.01575.2011
    CrossrefPubMedGoogle Scholar
  • 38 Faustino-Rocha AI, Silva A, Gabriel J. et al. Long-term exercise training as a modulator of mammary cancer vascularization. Biomed Pharmacother 2016; 81: 273-280 doi:10.1016/j.biopha.2016.04.030
    CrossrefPubMedGoogle Scholar
  • 39 Garcia E, Becker VG, McCullough DJ. et al. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity. J Appl Physiol (1985) 2016; 121: 15-24 doi:10.1152/japplphysiol.00266.2016
    CrossrefPubMedGoogle Scholar
  • 40 Schadler KL, Thomas NJ, Galie PA. et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 2016; 7: 65429-65440 doi:10.18632/oncotarget.11748
    Google Scholar
  • 41 Betof AS, Lascola CD, Weitzel D. et al. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst 2015; 107: djv040 doi:10.1093/jnci/djv040
    CrossrefPubMedGoogle Scholar
  • 42 McCullough DJ, Nguyen LM, Siemann DW. et al. Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model. J Appl Physiol (1985) 2013; 115: 1846-1854 doi:10.1152/japplphysiol.00949.2013
    CrossrefPubMedGoogle Scholar
  • 43 McCullough DJ, Stabley JN, Siemann DW. et al. Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J Natl Cancer Inst 2014; 106: dju036 doi:10.1093/jnci/dju036
    CrossrefPubMedGoogle Scholar
  • 44 Morrell MBG, Alvarez-Florez C, Zhang A. et al. Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma. Pediatr Blood Cancer 2019; 66: e27835 doi:10.1002/pbc.27835
    PubMedGoogle Scholar
  • 45 Jones LW, Viglianti BL, Tashjian JA. et al. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol (1985) 2010; 108: 343-348 doi:10.1152/japplphysiol.00424.2009
    CrossrefPubMedGoogle Scholar
  • 46 Alvarado A, Gil da Costa RM, Faustino-Rocha AI. et al. Effects of exercise training on breast cancer metastasis in a rat model. Int J Exp Pathol 2017; 98: 40-46 doi:10.1111/iep.12225
    CrossrefPubMedGoogle Scholar
  • 47 Mancini M, Toker A. NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 2009; 9: 810-820 doi:10.1038/nrc2735
    CrossrefPubMedGoogle Scholar
  • 48 Rinne A, Banach K, Blatter LA. Regulation of nuclear factor of activated T cells (NFAT) in vascular endothelial cells. J Mol Cell Cardiol 2009; 47: 400-410 doi:10.1016/j.yjmcc.2009.06.010
    CrossrefPubMedGoogle Scholar
  • 49 Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med 2012; 2: a006627 doi:10.1101/cshperspect.a006627
    CrossrefPubMedGoogle Scholar
  • 50 Klein D. The tumor vascular endothelium as decision maker in cancer therapy. Front Oncol 2018; 8: 367 doi:10.3389/fonc.2018.00367
    CrossrefPubMedGoogle Scholar
  • 51 Stylianopoulos T, Jain RK. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci USA 2013; 110: 18632-18637 doi:10.1073/pnas.1318415110
    CrossrefPubMedGoogle Scholar
  • 52 Cartier A, Leigh T, Liu CH. et al. Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy. Proc Natl Acad Sci USA 2020; 117: 3157-3166 doi:10.1073/pnas.1906246117
    CrossrefPubMedGoogle Scholar
  • 53 Hughes SK, Wacker BK, Kaneda MM. et al. Fluid shear stress modulates cell migration induced by sphingosine 1-phosphate and vascular endothelial growth factor. Ann Biomed Eng 2005; 33: 1003-1014 doi:10.1007/s10439-005-5756-1
    CrossrefPubMedGoogle Scholar
  • 54 Zhao J, Garcia D, Gartung A. et al. Sphingosine-1-phosphate receptor subtype 2 signaling in endothelial senescence-associated functional impairments and inflammation. Curr Atheroscler Rep 2015; 17: 504 doi:10.1007/s11883-015-0504-y
    CrossrefPubMedGoogle Scholar
  • 55 Jung B, Obinata H, Galvani S. et al. Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Dev Cell 2012; 23: 600-610 doi:10.1016/j.devcel.2012.07.015
    CrossrefPubMedGoogle Scholar
  • 56 Blankenbach KV, Schwalm S, Pfeilschifter J. et al. Sphingosine-1-phosphate receptor-2 antagonists: Therapeutic potential and potential risks. Front Pharmacol 2016; 7: 167 doi:10.3389/fphar.2016.00167
    CrossrefPubMedGoogle Scholar
  • 57 Schumacher O, Galvao DA, Taaffe DR. et al. Exercise modulation of tumour perfusion and hypoxia to improve radiotherapy response in prostate cancer. Prostate Cancer Prostatic Dis 2021; 24: 1-14 doi:10.1038/s41391-020-0245-z
    CrossrefPubMedGoogle Scholar
  • 58 van Kuijk SJ, Yaromina A, Houben R. et al. Prognostic significance of carbonic anhydrase IX expression in cancer patients: a meta-analysis. Front Oncol 2016; 6: 69 doi:10.3389/fonc.2016.00069
    CrossrefPubMedGoogle Scholar
  • 59 Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11: 393-410 doi:10.1038/nrc3064
    CrossrefPubMedGoogle Scholar
  • 60 Forster MJ, Dubey A, Dawson KM. et al. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA 1996; 93: 4765-4769 doi:10.1073/pnas.93.10.4765
    CrossrefPubMedGoogle Scholar
  • 61 Justice JN, Carter CS, Beck HJ. et al. Battery of behavioral tests in mice that models age-associated changes in human motor function. Age (Dordr) 2014; 36: 583-592 doi:10.1007/s11357-013-9589-9
    CrossrefPubMedGoogle Scholar
  • 62 Shoji H, Takao K, Hattori S. et al. Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. Mol Brain 2016; 9: 11 doi:10.1186/s13041-016-0191-9
    CrossrefPubMedGoogle Scholar
  • 63 Singhal G, Morgan J, Jawahar MC. et al. Effects of aging on the motor, cognitive and affective behaviors, neuroimmune responses and hippocampal gene expression. Behav Brain Res 2020; 383: 112501 doi:10.1016/j.bbr.2020.112501
    CrossrefPubMedGoogle Scholar
  • 64 Bartling B, Al-Robaiy S, Lehnich H. et al. Sex-related differences in the wheel-running activity of mice decline with increasing age. Exp Gerontol 2017; 87: 139-147 doi:10.1016/j.exger.2016.04.011
    CrossrefPubMedGoogle Scholar
  • 65 Fulop T, Kotb R, Fortin CF. et al. Potential role of immunosenescence in cancer development. Ann N Y Acad Sci 2010; 1197: 158-165 doi:10.1111/j.1749-6632.2009.05370.x
    CrossrefPubMedGoogle Scholar
  • 66 Wang Q, Zhou W. Roles and molecular mechanisms of physical exercise in cancer prevention and treatment. J Sport Health Sci 2021; 10: 201-210 doi:10.1016/j.jshs.2020.07.008
    Google Scholar
  • 67 Koteja P, Swallow JG, Carter PA. et al. Energy cost of wheel running in house mice: Implications for coadaptation of locomotion and energy budgets. Physiol Biochem Zool 1999; 72: 238-249 doi:10.1086/316653
    CrossrefPubMedGoogle Scholar
  • 68 Lightfoot JT, Turner MJ, Daves M. et al. Genetic influence on daily wheel running activity level. Physiol Genomics 2004; 19: 270-276 doi:10.1152/physiolgenomics.00125.2004
    CrossrefPubMedGoogle Scholar
  • 69 Lista P, Straface E, Brunelleschi S. et al. On the role of autophagy in human diseases: A gender perspective. J Cell Mol Med 2011; 15: 1443-1457 doi:10.1111/j.1582-4934.2011.01293.x
    CrossrefPubMedGoogle Scholar
  • 70 Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016; 16: 626-638 doi:10.1038/nri.2016.90
    CrossrefPubMedGoogle Scholar
  • 71 Cook MB, Dawsey SM, Freedman ND. et al. Sex disparities in cancer incidence by period and age. Cancer Epidemiol Biomarkers Prev 2009; 18: 1174-1182 doi:10.1158/1055-9965.EPI-08-1118
    CrossrefPubMedGoogle Scholar
  • 72 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69: 7-34 doi:10.3322/caac.21551
    CrossrefPubMedGoogle Scholar
  • 73 Torre LA, Bray F, Siegel RL. et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108 doi:10.3322/caac.21262
    CrossrefPubMedGoogle Scholar
  • 74 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29 doi:10.3322/caac.21254
    CrossrefPubMedGoogle Scholar
  • 75 Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 2010; 10: 594-604 doi:10.1038/nri2815
    CrossrefPubMedGoogle Scholar
  • 76 Hewagama A, Patel D, Yarlagadda S. et al. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 2009; 10: 509-516 doi:10.1038/gene.2009.12
    CrossrefPubMedGoogle Scholar
  • 77 Bouman A, Schipper M, Heineman MJ. et al. Gender difference in the non-specific and specific immune response in humans. Am J Reprod Immunol 2004; 52: 19-26 doi:10.1111/j.1600-0897.2004.00177.x
    CrossrefPubMedGoogle Scholar
  • 78 Gillum TL, Kuennen MR, Schneider S. et al. A review of sex differences in immune function after aerobic exercise. Exerc Immunol Rev 2011; 17: 104-121
    PubMedGoogle Scholar
  • 79 Gubbels Bupp MR. Sex, the aging immune system, and chronic disease. Cell Immunol 2015; 294: 102-110 doi:10.1016/j.cellimm.2015.02.002
    CrossrefPubMedGoogle Scholar
  • 80 Pedersen L, Idorn M, Olofsson GH. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab 2016; 23: 554-562 doi:10.1016/j.cmet.2016.01.011
    CrossrefPubMedGoogle Scholar
  • 81 Edwards KM, Burns VE, Ring C. et al. Individual differences in the interleukin-6 response to maximal and submaximal exercise tasks. J Sports Sci 2006; 24: 855-862 doi:10.1080/02640410500245645
    CrossrefPubMedGoogle Scholar
  • 82 Rubin JB, Lagas JS, Broestl L. et al. Sex differences in cancer mechanisms. Biol Sex Differ 2020; 11: 17 doi:10.1186/s13293-020-00291-x
    CrossrefPubMedGoogle Scholar
  • 83 Ashcraft KA, Peace RM, Betof AS. et al. 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: 4032-4050 doi:10.1158/0008-5472.CAN-16-0887
    CrossrefPubMedGoogle Scholar
  • 84 Pedersen L, Christensen JF, Hojman P. Effects of exercise on tumor physiology and metabolism. Cancer J 2015; 21: 111-116 doi:10.1097/PPO.0000000000000096
    CrossrefPubMedGoogle Scholar
  • 85 Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell 2017; 168: 670-691 doi:10.1016/j.cell.2016.11.037
    CrossrefPubMedGoogle Scholar
  • 86 Oliver AJ, Lau PKH, Unsworth AS. et al. Tissue-dependent tumor microenvironments and their impact on immunotherapy responses. Front Immunol 2018; 9: 70 doi:10.3389/fimmu.2018.00070
    CrossrefPubMedGoogle Scholar
  • 87 Choudhury A, Moniaux N, Ulrich AB. et al. MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFbeta2. Br J Cancer 2004; 90: 657-664 doi:10.1038/sj.bjc.6601604
    CrossrefPubMedGoogle Scholar
  • 88 Hoover M, Adamian Y, Brown M. et al. A novel method for RNA extraction from FFPE samples reveals significant differences in biomarker expression between orthotopic and subcutaneous pancreatic cancer patient-derived xenografts. Oncotarget 2017; 8: 5885-5894 doi:10.18632/oncotarget.11809
    CrossrefPubMedGoogle Scholar
  • 89 Zhan B, Wen S, Lu J. et al. Identification and causes of metabonomic difference between orthotopic and subcutaneous xenograft of pancreatic cancer. Oncotarget 2017; 8: 61264-61281 doi:10.18632/oncotarget.18057
    CrossrefPubMedGoogle Scholar
  • 90 Zhao X, Li L, Starr TK. et al. Tumor location impacts immune response in mouse models of colon cancer. Oncotarget 2017; 8: 54775-54787 doi:10.18632/oncotarget.18423
    CrossrefPubMedGoogle Scholar
  • 91 Brand M, Laban S, Theodoraki MN. et al. Characterization and differentiation of the tumor microenvironment (TME) of orthotopic and subcutaneously grown head and neck squamous cell carcinoma (HNSCC) in immunocompetent mice. Int J Mol Sci 2020; 22: 247 doi:10.3390/ijms22010247
    CrossrefPubMedGoogle Scholar
  • 92 Wettersten HI, Ganti S, Weiss RH. Metabolomic profiling of tumor-bearing mice. Methods Enzymol 2014; 543: 275-296 doi:10.1016/B978-0-12-801329-8.00014-3
    CrossrefPubMedGoogle Scholar
  • 93 Tian H, Lyu Y, Yang YG. et al. Humanized rodent models for cancer research. Front Oncol 2020; 10: 1696 doi:10.3389/fonc.2020.01696
    CrossrefPubMedGoogle Scholar
  • 94 Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol 2007; 7: 118-130 doi:10.1038/nri2017
    CrossrefPubMedGoogle Scholar
  • 95 Bosma MJ, Carroll AM. The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol 1991; 9: 323-350 doi:10.1146/annurev.iy.09.040191.001543
    CrossrefPubMedGoogle Scholar
  • 96 Piercy KL, Troiano RP, Ballard RM. et al. The physical activity guidelines for Americans. JAMA 2018; 320: 2020-2028 doi:10.1001/jama.2018.14854
    CrossrefPubMedGoogle Scholar
  • 97 Pollan M, Casla-Barrio S, Alfaro J. et al. Exercise and cancer: a position statement from the Spanish Society of Medical Oncology. Clin Transl Oncol 2020; 22: 1710-1729 doi:10.1007/s12094-020-02312-y
    CrossrefPubMedGoogle Scholar
  • 98 Cormie P, Zopf EM, Zhang X. et al. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Epidemiol Rev 2017; 39: 71-92 doi:10.1093/epirev/mxx007
    CrossrefPubMedGoogle Scholar
  • 99 Kruger K, Lechtermann A, Fobker M. et al. Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms. Brain Behav Immun 2008; 22: 324-338 doi:10.1016/j.bbi.2007.08.008
    CrossrefPubMedGoogle Scholar
  • 100 Benschop RJ, Nijkamp FP, Ballieux RE. et al. The effects of beta-adrenoceptor stimulation on adhesion of human natural killer cells to cultured endothelium. Br J Pharmacol 1994; 113: 1311-1316 doi:10.1111/j.1476-5381.1994.tb17141.x
    CrossrefPubMedGoogle Scholar
  • 101 Dimitrov S, Lange T, Born J. Selective mobilization of cytotoxic leukocytes by epinephrine. J Immunol 2010; 184: 503-511 doi:10.4049/jimmunol.0902189
    CrossrefPubMedGoogle Scholar
  • 102 Campbell JP, Riddell NE, Burns VE. et al. Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype. Brain Behav Immun 2009; 23: 767-775 doi:10.1016/j.bbi.2009.02.011
    CrossrefPubMedGoogle Scholar
  • 103 Turner JE, Spielmann G, Wadley AJ. et al. Exercise-induced B cell mobilisation: preliminary evidence for an influx of immature cells into the bloodstream. Physiol Behav 2016; 164: 376-382 doi:10.1016/j.physbeh.2016.06.023
    CrossrefPubMedGoogle Scholar
  • 104 Kruger K, Alack K, Ringseis R. et al. Apoptosis of T-cell subsets after acute high-intensity interval exercise. Med Sci Sports Exerc 2016; 48: 2021-2029 doi:10.1249/MSS.0000000000000979
    CrossrefPubMedGoogle Scholar
  • 105 Adams GR, Zaldivar FP, Nance DM. et al. Exercise and leukocyte interchange among central circulation, lung, spleen, and muscle. Brain Behav Immun 2011; 25: 658-666 doi:10.1016/j.bbi.2011.01.002
    CrossrefPubMedGoogle Scholar
  • 106 Sitlinger A, Brander DM, Bartlett DB. Impact of exercise on the immune system and outcomes in hematologic malignancies. Blood Adv 2020; 4: 1801-1811 doi:10.1182/bloodadvances.2019001317
    CrossrefPubMedGoogle Scholar
  • 107 Idorn M, Hojman P. Exercise-dependent regulation of NK cells in cancer protection. Trends Mol Med 2016; 22: 565-577 doi:10.1016/j.molmed.2016.05.007
    CrossrefPubMedGoogle Scholar
  • 108 Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 2008; 13: 21-26 doi:10.1634/theoncologist.13-S3-21
    CrossrefPubMedGoogle Scholar
  • 109 Rowell LB. Human cardiovascular adjustments to exercise and thermal stress. Physiol Rev 1974; 54: 75-159 doi:10.1152/physrev.1974.54.1.75
    CrossrefPubMedGoogle Scholar
  • 110 Smeda M, Przyborowski K, Proniewski B. et al. Breast cancer pulmonary metastasis is increased in mice undertaking spontaneous physical training in the running wheel; a call for revising beneficial effects of exercise on cancer progression. Am J Cancer Res 2017; 7: 1926-1936
    Google Scholar
  • 111 Goh J, Ladiges W. Voluntary wheel running in mice. Curr Protoc Mouse Biol 2015; 5: 283-290 doi:10.1002/9780470942390.mo140295
    Google Scholar
  • 112 Brown DA, Johnson MS, Armstrong CJ. et al. Short-term treadmill running in the rat: what kind of stressor is it?. J Appl Physiol (1985) 2007; 103: 1979-1985 doi:10.1152/japplphysiol.00706.2007
    CrossrefPubMedGoogle Scholar
  • 113 Ader R, Cohen N, Felten D. Psychoneuroimmunology: Interactions between the nervous system and the immune system. Lancet 1995; 345: 99-103 doi:10.1016/s0140-6736(95)90066-7
    CrossrefPubMedGoogle Scholar
  • 114 Lewis DI, Coote JH. Excitation and inhibition of rat sympathetic preganglionic neurones by catecholamines. Brain Res 1990; 530: 229-234 doi:10.1016/0006-8993(90)91287-q
    CrossrefPubMedGoogle Scholar
  • 115 Unnerstall JR, Kopajtic TA, Kuhar MJ. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: Analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res 1984; 319: 69-101 doi:10.1016/0165-0173(84)90030-4
    CrossrefPubMedGoogle Scholar
  • 116 Won E, Kim YK. Stress, the autonomic nervous system, and the immune-kynurenine pathway in the etiology of depression. Curr Neuropharmacol 2016; 14: 665-673 doi:10.2174/1570159x14666151208113006
    CrossrefPubMedGoogle Scholar
  • 117 Goel S, Duda DG, Xu L. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011; 91: 1071-1121 doi:10.1152/physrev.00038.2010
    CrossrefPubMedGoogle Scholar
  • 118 Joisten N, Schenk A, Zimmer P. Talking about physical "activity" or "inactivity"? The need of accurate activity controlling in exercise studies in rodents. Front Physiol 2020; 11: 611193 doi:10.3389/fphys.2020.611193
    Google Scholar
  • 119 Cox KL, Cyarto EV, Etherton-Beer C. et al. A randomized controlled trial of physical activity with individual goal-setting and volunteer mentors to overcome sedentary lifestyle in older adults at risk of cognitive decline: the INDIGO trial protocol. BMC Geriatr 2017; 17: 215 doi:10.1186/s12877-017-0617-y
    CrossrefPubMedGoogle Scholar
  • 120 Arikawa AY, O'Dougherty M, Kaufman BC. et al. Women in Steady Exercise Research (WISER): study design and methods. Contemp Clin Trials 2010; 31: 457-465 doi:10.1016/j.cct.2010.05.008
    CrossrefPubMedGoogle Scholar
  • 121 Amaro-Gahete FJ, De-la OA, Jurado-Fasoli L. et al. Metabolic rate in sedentary adults, following different exercise training interventions: The FIT-AGEING randomized controlled trial. Clin Nutr 2020; 39: 3230-3240 doi:10.1016/j.clnu.2020.02.001
    CrossrefPubMedGoogle Scholar
  • 122 Harriss DJ, MacSween A, Atkinson G. Ethical standards in sport and exercise science research: 2020 update. Int J Sports Med 2019; 40: 813-817 doi:10.1055/a-1015-3123
    Article in Thieme ConnectPubMedGoogle Scholar