期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 6, 期 250, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3009569
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资金
- RCN
- Medical Faculty of NTNU
- Central Norway Regional Health Authority
- NTNU
- U.S. NIH [1U54CA126513, RO1CA093405, RO1CA120979]
- Clyde Wu Family Foundation
- Mitsukoshi Health and Welfare Foundation
- Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad
- Uehara Memorial Foundation
- FUGE of RCN
- European Union [266408]
- St. Olavs Hospital
- German Research Foundation
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 M-3 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 M-3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.
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