期刊
CANCER CELL
卷 31, 期 1, 页码 21-34出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.11.005
关键词
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资金
- NIH [U54CA163004, R01CA093405, RO1DK097016, UO1DK103155, R01DK052778]
- Clyde Wu Family Foundation
- Nakayama Cancer Research Institute
- Okinaka Memorial Institute for Medical Research
- Project for Cancer Research And Therapeutic Evolution (P-CREATE) from the Japan Agency of Medical Research and Development, AMED
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation
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.
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