Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.
Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.
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DOI：
10.1016/j.ccell.2016.11.005
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发表时间：
2017-01-09
期刊：
影响因子：
50.3
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
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
在胃肠道干细胞生态位内，神经有助于调节正常和肿瘤干细胞的动态。在这里，我们揭示了癌症-神经伙伴关系的潜在机制。我们发现Dclk 1+丛细胞和神经是胃粘膜内乙酰胆碱（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，继而NGF在胃上皮内的过度表达扩张肠神经并促进癌变。Dclk 1+细胞的消融或NGF/Trk信号传导的阻断以毒蕈碱乙酰胆碱受体3（M3 R）依赖性方式抑制上皮增殖和肿瘤发生，部分通过抑制Yes相关蛋白（雅普）功能。这种前馈的ACh-NGF轴激活了胃癌的小生境，为肿瘤的治疗和预防提供了一个引人注目的靶点。
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 a muscarinic acetylcholine receptor-3 (M3R)-dependent manner, in part through suppression of Yes-Associated Protein (YAP) function. This feed-forward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.