title: Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.
abstract: Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Pedersen
authors.affiliation: Centre for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital, Herlev, DK-2730, Denmark.
authors.forename: Manja
authors.initials: M
authors.lastname: Idorn
authors.affiliation: Centre for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital, Herlev, DK-2730, Denmark.
authors.forename: Gitte H
authors.initials: GH
authors.lastname: Olofsson
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark.
authors.forename: Britt
authors.initials: B
authors.lastname: Lauenborg
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, SE-412, Sweden; Comparative Genomics Group, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.
authors.forename: Intawat
authors.initials: I
authors.lastname: Nookaew
authors.affiliation: Department of Radiology, University Hospital Copenhagen, Herlev, DK-2730, Denmark.
authors.forename: Rasmus Hvass
authors.initials: RH
authors.lastname: Hansen
authors.affiliation: Department of Radiology, University Hospital Copenhagen, Herlev, DK-2730, Denmark.
authors.forename: Helle Hjorth
authors.initials: HH
authors.lastname: Johannesen
authors.affiliation: Department for Translational Skin Cancer Research (TSCR) within the German Cancer Consortium (DKTK), Westdeutsches Tumorzentrum, University Hospital Essen, 45117, Essen, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark.
authors.forename: Katrine S
authors.initials: KS
authors.lastname: Pedersen
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Dethlefsen
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, SE-412, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Herlev, DK-2730, Denmark.
authors.forename: Julie
authors.initials: J
authors.lastname: Gehl
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark.
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: Centre for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital, Herlev, DK-2730, Denmark; Department of Immunology and Microbiology, University of Copenhagen, DK-2200, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Thor Straten
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Faculty of Health Science, University of Copenhagen, DK-2100, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, DK-2730, Denmark. Electronic address: phojman@inflammation-metabolism.dk.
authors.forename: Pernille
authors.initials: P
authors.lastname: Hojman
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000276:immunology; D045744:Cell Line, Tumor; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012420:Running; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D015850:Interleukin-6; D004837:Epinephrine
keywords: Physical activity; adrenalin; cancer; epinephrine; exercise; exercise oncology; immune cells; interleukin 6; natural killer cells