Geisler Fabian, Strazzabosco Mario
Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Hepatology. 2015 Jan;61(1):382-92. doi: 10.1002/hep.27268. Epub 2014 Sep 19.
This review critically discusses the most recent advances in the role of Notch signaling in liver development, homeostasis, and disease. It is now clear that the significance of Notch in determining mammalian cell fates and functions extends beyond development, and Notch is a major regular of organ homeostasis. Moreover, Notch signaling is reactivated upon injury and regulates the complex interactions between the distinct liver cell types involved in the repair process. Notch is also involved in the regulation of liver metabolism, inflammation, and cancer. The net effects of Notch signaling are highly variable and finely regulated at multiple levels, but also depend on the specific cellular context in which Notch is activated. Persistent activation of Notch signaling is associated with liver malignancies, such as hepatocellular carcinoma with stem cell features and intrahepatic cholangiocarcinoma. The complexity of the pathway provides several possible targets for agents able to inhibit Notch. However, further cell- and context-specific in-depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into clinical practice and be able to predict benefits and risks of evolving therapies.
本综述批判性地讨论了Notch信号通路在肝脏发育、稳态及疾病中的最新进展。现在已经明确，Notch在决定哺乳动物细胞命运和功能方面的重要性不仅限于发育阶段，而且是器官稳态的主要调节因子。此外，Notch信号通路在损伤后被重新激活，并调节参与修复过程的不同肝细胞类型之间的复杂相互作用。Notch还参与肝脏代谢、炎症和癌症的调节。Notch信号通路的净效应在多个水平上高度可变且受到精细调节，但也取决于Notch被激活的特定细胞环境。Notch信号通路的持续激活与肝脏恶性肿瘤有关，如具有干细胞特征的肝细胞癌和肝内胆管癌。该信号通路的复杂性为能够抑制Notch的药物提供了几个可能的靶点。然而，要将这些概念转化为临床实践，并能够预测不断发展的治疗方法的益处和风险，进一步对肝脏稳态和疾病中Notch信号通路进行细胞和背景特异性的深入了解至关重要。
