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

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 LinMichael D. Gershon, Akira Hara, Chun Mei Zhao, Duan Chen, Daniel L. Worthley, Kazuhiko Koike, Timothy C. Wang

Department of Internal Medicine II - Gastroenterology

Research output: Contribution to journal › Article › peer-review

377 Scopus citations

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.

Original language	English
Pages (from-to)	21-34
Number of pages	14
Journal	Cancer Cell
Volume	31
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.11.005
State	Published - 9 Jan 2017

Keywords

Dclk1
Lgr5
NGF
YAP
acetylcholine
gastric cancer
muscarinic acetylcholine receptor type 3
stem cell
tuft cell
wnt

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2016.11.005

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Hayakawa, Y., Sakitani, K., Konishi, M., Asfaha, S., Niikura, R., Tomita, H., Renz, B. W., Tailor, Y., Macchini, M., Middelhoff, M., Jiang, Z., Tanaka, T., Dubeykovskaya, Z. A., Kim, W., Chen, X., Urbanska, A. M., Nagar, K., Westphalen, C. B., Quante, M., ... Wang, T. C. (2017). Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell, 31(1), 21-34. https://doi.org/10.1016/j.ccell.2016.11.005

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title = "Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling",

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",

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

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jan,

day = "9",

doi = "10.1016/j.ccell.2016.11.005",

language = "English",

volume = "31",

pages = "21--34",

journal = "Cancer Cell",

issn = "1535-6108",

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Hayakawa, Y, Sakitani, K, Konishi, M, Asfaha, S, Niikura, R, Tomita, H, Renz, BW, Tailor, Y, Macchini, M, Middelhoff, M, Jiang, Z, Tanaka, T, Dubeykovskaya, ZA, Kim, W, Chen, X, Urbanska, AM, Nagar, K, Westphalen, CB, Quante, M, Lin, CS, Gershon, MD, Hara, A, Zhao, CM, Chen, D, Worthley, DL, Koike, K & Wang, TC 2017, 'Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling', Cancer Cell, vol. 31, no. 1, pp. 21-34. https://doi.org/10.1016/j.ccell.2016.11.005

TY - JOUR

T1 - Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

AU - Hayakawa, Yoku

AU - Sakitani, Kosuke

AU - Konishi, Mitsuru

AU - Asfaha, Samuel

AU - Niikura, Ryota

AU - Tomita, Hiroyuki

AU - Renz, Bernhard W.

AU - Tailor, Yagnesh

AU - Macchini, Marina

AU - Middelhoff, Moritz

AU - Jiang, Zhengyu

AU - Tanaka, Takayuki

AU - Dubeykovskaya, Zinaida A.

AU - Kim, Woosook

AU - Chen, Xiaowei

AU - Urbanska, Aleksandra M.

AU - Nagar, Karan

AU - Westphalen, Christoph B.

AU - Quante, Michael

AU - Lin, Chyuan Sheng

AU - Gershon, Michael D.

AU - Hara, Akira

AU - Zhao, Chun Mei

AU - Chen, Duan

AU - Worthley, Daniel L.

AU - Koike, Kazuhiko

AU - Wang, Timothy C.

PY - 2017/1/9

Y1 - 2017/1/9

N2 - 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.

AB - 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.

KW - Dclk1

KW - Lgr5

KW - NGF

KW - YAP

KW - acetylcholine

KW - gastric cancer

KW - muscarinic acetylcholine receptor type 3

KW - stem cell

KW - tuft cell

KW - wnt

UR - http://www.scopus.com/inward/record.url?scp=85008318998&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.11.005

DO - 10.1016/j.ccell.2016.11.005

M3 - Article

C2 - 27989802

AN - SCOPUS:85008318998

SN - 1535-6108

VL - 31

SP - 21

EP - 34

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Abstract

Keywords

UN SDGs

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