神经生长因子通过异常胆碱能信号传导促进胃癌发生。
Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.
作者信息
Hayakawa Yoku, Sakitani Kosuke, Konishi Mitsuru, Asfaha Samuel, Niikura Ryota, Tomita Hiroyuki, Renz Bernhard W, Tailor Yagnesh, Macchini Marina, Middelhoff Moritz, Jiang Zhengyu, Tanaka Takayuki, Dubeykovskaya Zinaida A, Kim Woosook, Chen Xiaowei, Urbanska Aleksandra M, Nagar Karan, Westphalen Christoph B, Quante Michael, Lin Chyuan-Sheng, Gershon Michael D, Hara Akira, Zhao Chun-Mei, Chen Duan, Worthley Daniel L, Koike Kazuhiko, Wang Timothy C
机构信息
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
出版信息
Cancer Cell. 2017 Jan 9;31(1):21-34. doi: 10.1016/j.ccell.2016.11.005. Epub 2016 Dec 15.
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.
在胃肠道干细胞生态位中，神经有助于调节正常和肿瘤性干细胞的动态变化。在此，我们揭示了癌症与神经伙伴关系背后的机制。我们发现，双皮质素样激酶1（Dclk1）簇状细胞和神经是胃黏膜中乙酰胆碱（ACh）的主要来源。胃上皮的胆碱能刺激诱导神经生长因子（NGF）表达，反过来，胃上皮内NGF的过表达会使肠神经扩张并促进肿瘤发生。Dclk1细胞的消融或NGF/酪氨酸激酶受体（Trk）信号的阻断以乙酰胆碱毒蕈碱受体-3（M3R）依赖的方式抑制上皮增殖和肿瘤发生，部分是通过抑制Yes相关蛋白（YAP）的功能。这种前馈性的ACh-NGF轴激活了胃癌生态位，并为肿瘤治疗和预防提供了一个极具吸引力的靶点。
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