Nerve Growth Factor Drives Gastric Tumorigenesis via Acetylcholine

The enteric nervous system, which is located within the walls of the gastrointestinal (GI) tract, directly and indirectly regulates mucosal regeneration by driving cholinergic signaling in muscarinic receptor–positive crypt cells and by interacting with stem-like doublecortin-like kinase 1–positive (DCLK1⁺) tuft cells, respectively. Recently, nerves have been shown to infiltrate the tumor microenvironment and release neurotransmitters, such as acetylcholine, to promote tumor growth; reciprocally, tumors secrete neurotrophic factors, such as nerve growth factor (NGF), which signal through neurotrophic receptor tyrosine kinases (NTRK) to stimulate nerve outgrowth and cancer cell growth. To elucidate the role of tuft cells in nerve–cancer cell cross-talk, Hayakawa, Sakitani, and colleagues interrogated acetylcholine signaling in transgenic mouse models. In a carcinogen-induced mouse model of gastric cancer, an increase in tuft cells expressing choline acetyltransferase (ChAT), which is responsible for acetylcholine synthesis, occurred during the early stages of tumorigenesis, followed by subsequent loss of ChAT⁺ tuft cells and increased axonal growth of cholinergic nerves. Collectively, these changes resulted in increased acetylcholine production and signaling, which induced the upregulation of NGF in gastric epithelial cells and tumors. Analysis of transgenic mouse models that conditionally express NGF or ablate the muscarinic receptor 3 (M3R) in mouse gastric epithelium showed that NGF promoted axonogenesis, M3R-mediated cholinergic signaling in tuft cells regulated mucosal proliferation and the expansion of clonal stem cells, and the NGF/cholinergic signaling axis stimulated GI dysplasia and tumor initiation. Consistent with these findings, inhibition of NGF reduced allograft tumor growth and innervation of the peritumoral mucosa in an NTRK-dependent manner. Mechanistically, NGF-driven upregulation of M3R-mediated cholinergic signaling promoted YAP activation to drive WNT signaling in APC-dependent tumor growth. Taken together, these findings further elucidate the acetylcholine-dependent signaling axis underlying gastric tumor initiation by nerve–cancer cell cross-talk and suggest that targeting this pathway may be a potential therapeutic strategy for patients with GI cancers.

Hayakawa Y, Sakitani K, Konishi M, Asfaha S, Niikura R, Tomita H, et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 2016;31:21–34.

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