Emerging roles of Notch signaling in liver disease

Abstract

This review critically discusses the most recent advances on 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 cellular 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 the clinical practice and be able to predict benefits and risks of evolving therapies.

Lineage fate of ductular reactions in liver injury and carcinogenesis

“…This supports the concept that the biliary fate of DDC-induced DRs is firmly fixed and that NOTCH signaling and WNT/β-catenin determine cellular cues for effective DR proliferation and morphogenesis (7,12,48), rather than for DRC lineage allocation. Our findings that neoplastic lesions did not arise from the biliary HNF1β lineage in two distinct, commonly used HCC mouse models further fits in this overall picture of limited plastic capacity of postnatal biliary cells and highly suggests that hepatocytes are the primary cell type susceptive to malignant transformation in hepatocellular carcinogenesis.…”

“…It is widely believed that such putative progenitors serve as an adult emergency compartment capable of producing both cholangiocytes and hepatocytes in case acute or chronic liver injury compromises self-duplication of these mature epithelial cells. While the biliary fate is considered the "default setting" of DRCs determined by juxtacrine NOTCH activation, paracrine activation of β-catenin by WNT proteins may alter the fate of biliary-derived DRCs such that they become hepatocytes (10)(11)(12). In line with this concept of DRCs physiologically acting as bipotential progenitors, cells isolated from DRs can self-renew, give rise to biliary cells and hepatocytes in vitro, and regenerate hepatocytes with variable success when transplanted into Fah -/-mice, a mouse model of hereditary tyrosinemia type 1 (13)(14)(15)(16)).…”

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

“…There is increasing evidence that aberrant Notch pathway activation occurs in solid tumors, including liver cancers (36). In clinical hepatocellular carcinoma tumor tissues, upregulation of Notch components has been observed, which is significantly associated with disease progression such as tumor metastasis (22).…”

“…These studies also suggest that persistent activation of the Notch signaling might play roles both in reprograming hepatic progenitor cells (HPC) into CSCs and in maintaining CSC features during hepatocellular carcinoma development (36). In our study design, the experiment was performed on liver cancer spheres, which enrich the hepatocellular carcinoma CSC population (25), and the in vivo orthotopic tumor model was also generated from hepatocellular carcinoma cancer spheres.…”

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

“…6 Notch receptors and ligands are constitutively expressed in various human tissues, including the liver. 2 Mutations in the JAG1 or NOTCH2 genes cause Alagille syndrome, a multisystemic congenital disease characterized by defective development of interlobular bile ducts and vessel architecture. 7,8 Most patients with Alagille syndrome do not develop overt fibrosis.…”