Neurotransmitters have been shown to drive tumor progression in the prostate glands and the stomach. In particular, it has recently been shown that acetylcholine promotes proliferation of Lgr5-positive cancer stem cells via the modulation of YAP-dependent canonical Wnt/beta-catenin signal pathway. Then the secretion of NGF occurs. This forms the positive feedback machinery. Is there any clinical method to demonstrate the denervation in the tumor tissues?
Hayakawa et al. have demonstrated a feed-forward signaling loop between cholinergic nerves and enteric cancer cells, whereby Ach (from tuft cells initially and from recruited gastric nerves later in tumor progression) promotes NGF expression by the tumor and this NGF secretion induces the generation of new neurons (also referred to as axonogenesis), increased tumor innervation, and subsequent Ach release.
Article Nerve Growth Factor Promotes Gastric Tumorigenesis through A...
Denervation was once used to reduce acid output in ulcer disease, of the pyloric region, the one where the feedback signals that stimulate acid secretion come from. When the anti-histamines and -prazoles came in, this 'functional' gastric surgery was abandoned, and also the number of gastric surgery reduced, as complications from ulcer disease tended to zero. The term 'Gastric cancer' is so wide that it seems difficult giving a comprehensive response to the question, even more, I'm not a surgeon, but the question has interesting basic science connections. Prostaglandines, perhaps specially PGE2, have an important role in the functioning, multiplication, and transformed gastric cell growth. Thanks, regards, + Salut
Thank you Joe, and the denervatioon would reduce the tumor growth and development including invasion and metastasis in mouse experiments. The histological characteristics of the gastric tumor used in the experiment (the above paper) was the typical well-differentiated gastric adenocarcinoma. Tumor cells crosstalk with (or "educate") neurons to activate their own canonical Wnt signal pathway to proliferate via M3R.
Denervation suppresses gastric tumorigenesis
Chun-Mei Zhao,#1 Yoku Hayakawa,#2 Yosuke Kodama,1 Sureshkumar Muthupalani,3 Christoph B. Westphalen,2,4 Gøran T. Andersen,1,5 Arnar Flatberg,1 Helene Johannessen,1 Richard A. Friedman,6 Bernhard W. Renz,2 Arne K. Sandvik,1,7Vidar Beisvag,1 Hiroyuki Tomita,8 Akira Hara,8 Michael Quante,9 Zhishan Li,10 Michael D. Gershon,10 Kazuhiro Kaneko,11 James G. Fox,3 Timothy C. Wang,2,† and Duan Chen1,†
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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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374618/
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