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

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.

Author information

1
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
2
Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
3
Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.
4
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 5011194, Japan.
5
Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, 81377, Germany.
6
Department of Internal Medicine III, Klinikum der Universität München, Munich, 81377, Germany.
7
Department of Internal Medicine II, Klinikum rechts der Isar, II. Technische Universität München, Munich, 81675, Germany.
8
Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
9
Transgenic Mouse Shared Resource, Columbia University, New York, NY, 10032, USA.
10
Department of Cancer Research and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Trondheim, 7491, Norway.
11
Cancer theme, SAHMRI and Department of Medicine, University of Adelaide, SA, 5000, Australia.
#
Contributed equally

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

PMID:
27989802
PMCID:
PMC5225031
DOI:
10.1016/j.ccell.2016.11.005
[Indexed for MEDLINE]
Free PMC Article

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