TY - JOUR
T1 - Denervation suppresses gastric tumorigenesis
AU - Zhao, Chun Mei
AU - Hayakawa, Yoku
AU - Kodama, Yosuke
AU - Muthupalani, Sureshkumar
AU - Westphalen, Christoph B.
AU - Andersen, Gøran T.
AU - Flatberg, Arnar
AU - Johannessen, Helene
AU - Friedman, Richard A.
AU - Renz, Bernhard W.
AU - Sandvik, Arne K.
AU - Beisvag, Vidar
AU - Tomita, Hiroyuki
AU - Hara, Akira
AU - Quante, Michael
AU - Li, Zhishan
AU - Gershon, Michael D.
AU - Kaneko, Kazuhiro
AU - Fox, James G.
AU - Wang, Timothy C.
AU - Chen, Duan
N1 - Publisher Copyright:
© 2014, American Association for the Advancement of Science. All rights reserved.
PY - 2014/8/20
Y1 - 2014/8/20
N2 - 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 M3receptor 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.
AB - 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 M3receptor 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.
UR - http://www.scopus.com/inward/record.url?scp=84907395110&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3009569
DO - 10.1126/scitranslmed.3009569
M3 - Article
C2 - 25143365
AN - SCOPUS:84907395110
SN - 1946-6234
VL - 6
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 250
M1 - 250ra115
ER -
