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Sci Transl Med. 2014 Aug 20;6(250):250ra115. doi: 10.1126/scitranslmed.3009569.

Denervation suppresses gastric tumorigenesis.

Author information

1
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
2
Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032-3802, USA.
3
Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA 02139, USA.
4
Medizinische Klinik III, Klinikum der Universität München, Campus Grobhadern, 81377 München, Germany.
5
Department of Surgery, St. Olavs University Hospital, Trondheim 7006, Norway.
6
Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
7
Department of Gastrointestinal and Liver Diseases, St. Olavs University Hospital, Trondheim 7006, Norway.
8
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1112, Japan.
9
II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München 81675, Germany.
10
Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
11
Department of Gastroenterology and Endoscopy Division, National Cancer Center Hospital East, Chiba 277-8577, Japan.
#
Contributed equally

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.

PMID:
25143365
PMCID:
PMC4374618
DOI:
10.1126/scitranslmed.3009569
[Indexed for MEDLINE]
Free PMC Article

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