title: Denervation suppresses gastric tumorigenesis.
abstract: The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Zhao
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA 02139, USA.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.|Medizinische Klinik III, Klinikum der Universität München, Campus Grobhadern, 81377 München, Germany.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.|Department of Surgery, St. Olavs University Hospital, Trondheim 7006, Norway.
authors.forename: Gøran T
authors.initials: GT
authors.lastname: Andersen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Arnar
authors.initials: A
authors.lastname: Flatberg
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Helene
authors.initials: H
authors.lastname: Johannessen
authors.affiliation: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Renz
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.|Department of Gastrointestinal and Liver Diseases, St. Olavs University Hospital, Trondheim 7006, Norway.
authors.forename: Arne K
authors.initials: AK
authors.lastname: Sandvik
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Vidar
authors.initials: V
authors.lastname: Beisvag
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1112, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1112, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München 81675, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
authors.affiliation: Department of Gastroenterology and Endoscopy Division, National Cancer Center Hospital East, Chiba 277-8577, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA 02139, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: Duan
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D003714:Denervation; D004195:Disease Models, Animal; D018450:Disease Progression; D007249:Inflammation / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D064531:Peripherins / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D060449:Wnt Signaling Pathway
chemical_list: D014408:Biomarkers, Tumor; D064531:Peripherins; D043587:Receptor, Muscarinic M3