Denervation suppresses gastric tumorigenesis

ci Transl Med 20 August 2014: 
Vol. 6, Issue 250, p. 250ra115 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009569

• RESEARCH ARTICLE

CANCER

Denervation suppresses gastric tumorigenesis

1. Chun-Mei Zhao1,*, 
2. Yoku Hayakawa2,*, 
3. Yosuke Kodama1, 
4. Sureshkumar Muthupalani3,
5. Christoph B. Westphalen2,4, 
6. Gøran T. Andersen1,5, 
7. Arnar Flatberg1, 
8. Helene Johannessen1,
9. Richard A. Friedman6, 
10. Bernhard W. Renz2, 
11. Arne K. Sandvik1,7, 
12. Vidar Beisvag1, 
13. Hiroyuki Tomita8,
14. Akira Hara8, 
15. Michael Quante9, 
16. Zhishan Li10, 
17. Michael D. Gershon10, 
18. Kazuhiro Kaneko11, 
19. James G. Fox3,
20. Timothy C. Wang2,† and 
21. Duan Chen1,†

+Author Affiliations

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

+Author Notes

• ↵* These authors contributed equally to this work.

1. ↵†Corresponding authors. E-mails: duan.chen@ntnu.no (D.C.); tcw21@columbia.edu (T.C.W.)

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 M₃receptor–mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.

• Copyright © 2014, American Association for the Advancement of Science

Citation: C-M. Zhao, Y. Hayakawa, Y. Kodama, S. Muthupalani, C. B. Westphalen, G. T. Andersen, A. Flatberg, H. Johannessen, R. A. Friedman, B. W. Renz, A. K. Sandvik, V. Beisvag, H. Tomita, A. Hara, M. Quante, Z. Li, M. D. Gershon, K. Kaneko, J. G. Fox, T. C. Wang, D. Chen, Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 6, 250ra115 (2014).

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