| Literature DB >> 27989802 |
Yoku Hayakawa1,2, Kosuke Sakitani1, Mitsuru Konishi2, Samuel Asfaha1,3, Ryota Niikura2, Hiroyuki Tomita4, Bernhard W Renz1,5, Yagnesh Tailor1, Marina Macchini1, Moritz Middelhoff1, Zhengyu Jiang1, Takayuki Tanaka1, Zinaida A Dubeykovskaya1, Woosook Kim1, Xiaowei Chen1, Aleksandra M Urbanska1, Karan Nagar1, Christoph B Westphalen1,6, Michael Quante7, Chyuan-Sheng Lin8,9, Michael D Gershon8, Akira Hara4, Chun-Mei Zhao10, Duan Chen10, Daniel L Worthley1,11, Kazuhiko Koike2, Timothy C Wang1.
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.Entities:
Keywords: Dclk1; Lgr5; NGF; YAP; acetylcholine; gastric cancer; muscarinic acetylcholine receptor type 3; stem cell; tuft cell; wnt
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Year: 2016 PMID： 27989802 PMCID： PMC5225031 DOI： 10.1016/j.ccell.2016.11.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585