Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Authors

Yoku Hayakawa, Columbia University Irving Medical Center
Kosuke Sakitani, Columbia University Irving Medical Center
Mitsuru Konishi, Graduate School of Medicine
Samuel Asfaha, Columbia University Irving Medical CenterFollow
Ryota Niikura, Graduate School of Medicine
Hiroyuki Tomita, Graduate School of Medicine
Bernhard W. Renz, Columbia University Irving Medical Center
Yagnesh Tailor, Columbia University Irving Medical Center
Marina Macchini, Columbia University Irving Medical Center
Moritz Middelhoff, Columbia University Irving Medical Center
Zhengyu Jiang, Columbia University Irving Medical Center
Takayuki Tanaka, Columbia University Irving Medical Center
Zinaida A. Dubeykovskaya, Columbia University Irving Medical Center
Woosook Kim, Columbia University Irving Medical Center
Xiaowei Chen, Columbia University Irving Medical Center
Aleksandra M. Urbanska, Columbia University Irving Medical Center
Karan Nagar, Columbia University Irving Medical Center
Christoph B. Westphalen, Columbia University Irving Medical Center
Michael Quante, Klinik und Poliklinik für Innere Medizin II, Technische Universität München
Chyuan Sheng Lin, Columbia University
Michael D. Gershon, Columbia University
Akira Hara, Graduate School of Medicine
Chun Mei Zhao, Norges Teknisk-Naturvitenskapelige Universitet
Duan Chen, Norges Teknisk-Naturvitenskapelige Universitet
Daniel L. Worthley, Columbia University Irving Medical Center
Kazuhiko Koike, Graduate School of Medicine
Timothy C. Wang, Columbia University Irving Medical Center

Document Type

Article

Publication Date

1-9-2017

Journal

Cancer Cell

Volume

31

Issue

1

First Page

21

Last Page

34

URL with Digital Object Identifier

10.1016/j.ccell.2016.11.005

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.