Ding Li, Han Lingling, Li Yin, Zhao Jing, He Ping, Zhang Weizhen
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China.
Neoplasia. 2014 Nov 20;16(11):909-17. doi: 10.1016/j.neo.2014.08.010. eCollection 2014 Nov.
The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1 (loxp/loxp) mice, we generated the Neurog3-Tsc1-/- transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1-/- mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.
结节性硬化症复合物（TSC）在胰腺癌发病机制中的作用在很大程度上仍不清楚。本研究表明，神经生成素3介导的Tsc1基因Cre缺失可诱导胰腺腺泡癌的发生。通过将Neurog3-cre小鼠与Tsc1（loxp/loxp）小鼠杂交，我们构建了Neurog3-Tsc1-/-转基因小鼠，其中Tsc1基因在胰腺祖细胞中被缺失，mTOR信号通路被激活。所有Neurog3-Tsc1-/-小鼠从100日龄开始在胰腺中出现明显的腺癌样病变。肿瘤病变由形态和分子特征与腺泡细胞相似的细胞组成。5%的动物检测到肿瘤转移至肝脏和肺。雷帕霉素抑制mTOR信号通路可显著减弱肿瘤生长。雷帕霉素治疗停止后14天内肿瘤复发。我们的研究表明，胰腺祖细胞中mTOR信号通路的激活可能触发腺泡癌的发生。因此，mTOR可能作为治疗胰腺腺泡癌的潜在靶点。
