Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Yoku Hayakawa, Kosuke Sakitani, Mitsuru Konishi, Samuel Asfaha, Ryota Niikura, Hiroyuki Tomita, Bernhard W. Renz, Yagnesh Tailor, Marina Macchini, Moritz Middelhoff, Zhengyu Jiang, Takayuki Tanaka, Zinaida A. Dubeykovskaya, Woosook Kim, Xiaowei Chen, Aleksandra M. Urbanska, Karan Nagar, Christoph B. Westphalen, Michael Quante, Chyuan Sheng LinMichael D. Gershon, Akira Hara, Chun Mei Zhao, Duan Chen, Daniel L. Worthley, Kazuhiko Koike, Timothy C. Wang

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21-34
Number of pages14
JournalCancer Cell
Volume31
Issue number1
DOIs
Publication statusPublished - 9 Jan 2017

Keywords

  • Dclk1
  • Lgr5
  • NGF
  • YAP
  • acetylcholine
  • gastric cancer
  • muscarinic acetylcholine receptor type 3
  • stem cell
  • tuft cell
  • wnt

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Hayakawa, Y., Sakitani, K., Konishi, M., Asfaha, S., Niikura, R., Tomita, H., ... Wang, T. C. (2017). Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell, 31(1), 21-34. https://doi.org/10.1016/j.ccell.2016.11.005