Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Yoku Hayakawa; Kosuke Sakitani; Mitsuru Konishi; Samuel Asfaha; Ryota Niikura; Hiroyuki Tomita; Bernhard W Renz; Yagnesh Tailor; Marina Macchini; Moritz Middelhoff; Zhengyu Jiang; Takayuki Tanaka; Zinaida A Dubeykovskaya; Woosook Kim; Xiaowei Chen; Aleksandra M Urbanska; Karan Nagar; Christoph B Westphalen; Michael Quante; Chyuan-Sheng Lin; Michael D Gershon; Akira Hara; Chun-Mei Zhao; Duan Chen; Daniel L Worthley; Kazuhiko Koike; Timothy C Wang

doi:10.1016/j.ccell.2016.11.005

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

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

Authors

Yoku Hayakawa^#^{1

2}, Kosuke Sakitani^#¹, Mitsuru Konishi², Samuel Asfaha^{1

3}, Ryota Niikura², Hiroyuki Tomita⁴, Bernhard W Renz^{1

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 Westphalen^{1

6}, Michael Quante⁷, Chyuan-Sheng Lin^{8

9}, Michael D Gershon⁸, Akira Hara⁴, Chun-Mei Zhao¹⁰, Duan Chen¹⁰, Daniel L Worthley^{1

11}, Kazuhiko Koike², Timothy C Wang¹

Affiliations

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.

MeSH terms

Acetylcholine / physiology*
Adaptor Proteins, Signal Transducing / physiology
Animals
Cell Cycle Proteins
Doublecortin-Like Kinases
Gastric Mucosa / innervation
Mice
Mice, Inbred C57BL
Nerve Growth Factor / physiology*
Phosphoproteins / physiology
Protein Serine-Threonine Kinases / analysis
Receptor, Muscarinic M3 / physiology
Signal Transduction / physiology*
Stomach Neoplasms / etiology*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Phosphoproteins
Receptor, Muscarinic M3
YAP-Signaling Proteins
Yap1 protein, mouse
Nerve Growth Factor
Doublecortin-Like Kinases
Dclk1 protein, mouse
Protein Serine-Threonine Kinases
Acetylcholine

Abstract

MeSH terms

Substances

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