Denervation suppresses gastric tumorigenesis
Top Cited Papers
Open Access
- 20 August 2014
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 6 (250), 250ra115
- https://doi.org/10.1126/scitranslmed.3009569
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.Keywords
This publication has 56 references indexed in Scilit:
- A restricted cell population propagates glioblastoma growth after chemotherapyNature, 2012
- Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondinsThe EMBO Journal, 2012
- Drugging Wnt signalling in cancerThe EMBO Journal, 2012
- Muscarinic Receptor Agonists and Antagonists: Effects on CancerPublished by Springer Science and Business Media LLC ,2011
- Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ miceCarcinogenesis: Integrative Cancer Research, 2011
- Inhibition of Gastric Carcinogenesis by the Hormone Gastrin Is Mediated by Suppression of TFF1 Epigenetic SilencingGastroenterology, 2011
- Paneth cells constitute the niche for Lgr5 stem cells in intestinal cryptsNature, 2010
- Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008International Journal of Cancer, 2010
- Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestineProceedings of the National Academy of Sciences of the United States of America, 2009
- Overexpression of Interleukin-1β Induces Gastric Inflammation and Cancer and Mobilizes Myeloid-Derived Suppressor Cells in MiceCancer Cell, 2008