Denervation suppresses gastric tumorigenesis

去神经支配 癌变 毒蕈碱乙酰胆碱受体 医学 癌症研究 内分泌学 内科学 癌症 病理 受体
作者
Chun‐Mei Zhao,Yoku Hayakawa,Yosuke Kodama,Sureshkumar Muthupalani,C. Benedikt Westphalen,Gøran Andersen,Arnar Flatberg,Helene Johannessen,Richard A. Friedman,Bernhard W. Renz,Arne K. Sandvik,Vidar Beisvåg,Hiroyuki Tomita,Akira Hara,Michael Quante,Zhishan Li,Michael D. Gershon,Kazuhiro Kaneko,James G. Fox,Timothy C. Wang
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:6 (250): 250ra115-250ra115 被引量:639
标识
DOI:10.1126/scitranslmed.3009569
摘要

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.
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