Denervation suppresses gastric tumorigenesis

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.

The role of perineural invasion in predicting survival in patients with primary operable colorectal cancer: A systematic review

“…Autonomic neurotransmitters can also stimulate endothelial cells, immune cells, and fibroblasts thus having an impact on the tumour microenvironment [51]. Moreover, it has recently been reported that nerves in prostate and gastric tumours, release neurotransmitters directly into the vicinity of cancer cells to stimulate survival, proliferation, and the ability to spread [52,53].…”

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

“…They proposed that sympathetic postganglionic neurons regulated the initiation of the disease, whereas postganglionic parasympathetic neurons were implicated in advanced disease. Zhao et al (52), used three models of gastric cancer and found that surgical vagotomy slowed and/or decreased tumor progression and increased the effectiveness of chemotherapy. Parasympathetic postganglionic neurons were also implicated based on changes in signaling pathways downstream of the type 3 muscarinic receptor expressed by these neurons, and that botox was able to slow tumor growth.…”

Gastric Cancer: A Stem Cell Disease?

“…In three independent mouse models of gastric cancer, Zhao et al elegantly demonstrated that surgical or pharmacological denervation suppresses gastric tumorigenesis, even if performed at an early preneoplastic step [21]. Further analyses revealed that cholinergic nerves surround the base of glands and modulate epithelial stem cells through activation of the Wnt signaling pathway via the muscarinic acetylcholine receptor 3 (M 3 R) expressed by Lgr5 + cells.…”

“…The Notch signaling pathway is also inhibited in vagotomized mice [21]. The Notch inhibitor dibenzazepine (DBZ) reduced the proliferation in the isthmus region, decreased the Mist1-lineage tracing, and blocked the growth of corpus organoids in vitro, suggesting that Notch activity is important for corpus gastric stem cell maintenance and activity [13].…”

“…Further analyses revealed that cholinergic nerves surround the base of glands and modulate epithelial stem cells through activation of the Wnt signaling pathway via the muscarinic acetylcholine receptor 3 (M 3 R) expressed by Lgr5 + cells. In stomach organoid models, coculture with neurons or treatment with pilocarpine, a cholinomimetic drug, increased organoid formation and the expression of Lgr5 and Cd44 stem cell markers, whereas the efects were reversed by botox treatment [21]. Another publication reported that Dclk1 + tuft cells and nerves, the main sources of acetylcholine in the gastric mucosa, induced nerve growth factor (NGF) secretion from epithelial cells that expand enteric nerves and promote carcinogenesis [22].…”