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Type: Journal article
Title: Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling
Author: Hayakawa, Y.
Sakitani, K.
Konishi, M.
Asfaha, S.
Niikura, R.
Tomita, H.
Renz, B.
Tailor, Y.
Macchini, M.
Middelhoff, M.
Jiang, Z.
Tanaka, T.
Dubeykovskaya, Z.
Kim, W.
Chen, X.
Urbanska, A.
Nagar, K.
Westphalen, C.
Quante, M.
Lin, C.
et al.
Citation: Cancer Cell, 2017; 31(1):21-34
Publisher: Cell Press
Issue Date: 2017
ISSN: 1535-6108
Statement of
Yoku Hayakawa ... Daniel L. Worthley ... et al.
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: NGF; gastric cancer; acetylcholine; Lgr5; wnt; YAP; Dclk1; tuft cell; stem cell; muscarinic acetylcholine receptor type 3
Rights: ©2017 Elsevier Inc.
DOI: 10.1016/j.ccell.2016.11.005
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