Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Cancer Cell. 2017 Jan 9;31(1):21-34. doi: 10.1016/j.ccell.2016.11.005. Epub 2016 Dec 15.

Abstract

Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.

Keywords: Dclk1; Lgr5; NGF; YAP; acetylcholine; gastric cancer; muscarinic acetylcholine receptor type 3; stem cell; tuft cell; wnt.

MeSH terms

  • Acetylcholine / physiology*
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Cell Cycle Proteins
  • Gastric Mucosa / innervation
  • Mice
  • Mice, Inbred C57BL
  • Nerve Growth Factor / physiology*
  • Phosphoproteins / physiology
  • Protein-Serine-Threonine Kinases / analysis
  • Receptor, Muscarinic M3 / physiology
  • Signal Transduction / physiology*
  • Stomach Neoplasms / etiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Receptor, Muscarinic M3
  • Yap1 protein, mouse
  • Nerve Growth Factor
  • Dclk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Acetylcholine