Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Publication date: Available online 15 December 2016
Source:Cancer Cell
Author(s): 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 Lin, Michael D. Gershon, Akira Hara, Chun-Mei Zhao, Duan Chen, Daniel L. Worthley, Kazuhiko Koike, Timothy C. Wang
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.

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Teaser

Hayakawa et al. use a series of mouse models to show that acetylcholine from Dclk1+ tuft cells and nerves induces NGF in gastric epithelial cells, which promotes neuron expansion and tumorigenesis. YAP is activated through the cholinergic signaling, and inhibition of this pathway can block NGF-driven tumors.


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