Vagal Innervation Is Necessary for Gastric Tumorigenesis

Autonomic nerves have been shown to regulate stem and progenitor cells and have recently been implicated in tumor development and progression. Surgical removal of the vagus nerve (vagotomy), which innervates the stomach, is associated with decreased cell proliferation and reduced risk of gastric cancer, prompting Zhao, Hayakawa, and colleagues to investigate the role of innervation in gastric tumorigenesis using genetically induced, chemically induced, or Helicobacter pylori–infected mouse models. Surgical denervation via vagotomy during the preneoplastic stage of tumorigenesis diminished tumor incidence and size and attenuated tumor cell proliferation specifically in the denervated portion of the stomach, suggesting that the vagus nerve promotes gastric cancer growth. Consistent with this idea, pharmacologic denervation via local administration of botulinum toxin A in the gastric wall similarly impaired preneoplastic growth. Furthermore, surgical or pharmacologic denervation at later stages of tumorigenesis suppressed gastric cancer progression and augmented the antitumor effect of chemotherapy in tumor-bearing mice, resulting in prolonged survival. This effect was mediated in part by inhibition of WNT signaling, which regulates gastrointestinal stem cells and tumor formation; denervation reduced the expression of WNT-regulated stem cell markers and decreased the expansion of leucine-rich repeat containing G protein–coupled receptor 5 –positive (LGR5⁺) stem cells in the gastric mucosa via activation of the muscarinic acetylcholine receptor 3 (M₃R) in LGR5⁺ stem cells. M₃R signaling stimulated ligand-independent WNT activation and enhanced the growth of gastric organoids in vitro, whereas deletion of M₃R or treatment with an M₃R inhibitor in combination with chemotherapy suppressed WNT signaling and reduced gastric tumor formation in mice. Importantly, in patients with gastric cancer, WNT signaling was associated with neural pathways and neuronal density was correlated with more advanced tumors. These findings identify nerves as important regulators of gastric stem cell expansion and tumor progression and suggest M₃R as a potential therapeutic target in gastric cancer.

Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med 2014;6:250ra115.