Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

被引：405

作者：

Hayakawa, Yoku ^{[1
,2
]}

Sakitani, Kosuke ^{[1
]}

Konishi, Mitsuru ^{[2
]}

Asfaha, Samuel ^{[1
,3
]}

Niikura, Ryota ^{[2
]}

Tomita, Hiroyuki ^{[4
]}

Renz, Bernhard W. ^{[1
,5
]}

Tailor, Yagnesh ^{[1
]}

Macchini, Marina ^{[1
]}

Middelhoff, Moritz ^{[1
]}

Jiang, Zhengyu ^{[1
]}

Tanaka, Takayuki ^{[1
]}

Dubeykovskaya, Zinaida A. ^{[1
]}

Kim, Woosook ^{[1
]}

Chen, Xiaowei ^{[1
]}

Urbanska, Aleksandra M. ^{[1
]}

Nagar, Karan ^{[1
]}

Westphalen, Christoph B. ^{[1
,6
]}

Quante, Michael ^{[7
]}

Lin, Chyuan-Sheng ^{[8
,9
]}

Gershon, Michael D. ^{[8
]}

Hara, Akira ^{[4
]}

Zhao, Chun-Mei ^{[10
]}

Chen, Duan ^{[10
]}

Worthley, Daniel L. ^{[11
,12
]}

Koike, Kazuhiko ^{[2
]}

Wang, Timothy C. ^{[1
]}

机构：

[1] Columbia Univ, Med Ctr, Irving Canc Res Ctr, Dept Med,Div Digest & Liver Dis, 1130 St Nicholas Ave, New York, NY 10032 USA

[2] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan

[3] Univ Western Ontario, Dept Med, London, ON N6A 5W9, Canada

[4] Gifu Univ, Dept Tumor Pathol, Grad Sch Med, Gifu 5011194, Japan

[5] Hosp Univ Munich, Dept Gen Visceral Transplantat Vasc & Thorac Surg, D-81377 Munich, Germany

[6] Klinikum Univ Munchen, Dept Internal Med 3, D-81377 Munich, Germany

[7] Tech Univ Munich, Klinikum Rechts Isar 2, Dept Internal Med 2, D-81675 Munich, Germany

[8] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA

[9] Columbia Univ, Transgen Mouse Shared Resource, New York, NY 10032 USA

[10] NTNU Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7491 Trondheim, Norway

[11] Univ Adelaide, SAHMRI, Canc Theme, Adelaide, SA 5005, Australia

[12] Univ Adelaide, Dept Med, Adelaide, SA 5005, Australia

来源：

CANCER CELL | 2017年 / 31卷 / 01期

基金：

日本学术振兴会;

关键词：

MUSCARINIC ACETYLCHOLINE-RECEPTORS; STEM-CELLS; INTRAEPITHELIAL NEOPLASIA; PROGENITOR CELLS; TRANSGENIC MICE; ENTERIC NEURONS; HAIR FOLLICLE; BONE-MARROW; BRUSH CELLS; GLIAL-CELLS;

D O I：

10.1016/j.ccell.2016.11.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：21 / 34

页数：14

共 66 条

[1] Cholinergically stimulated gastric acid secretion is mediated by M3 and M5 but not M1 muscarinic acetylcholine receptors in mice [J].