The roles of transforming growth factor-β, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours (Review)

Abstract

Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-β, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis.

Figure 1.

Schematic representation of the role of Wnt, Notch, TGF-β and Hif-1α signalling in hepatocytes, cholangiocytes and liver progenitor cells in hepatocarcinogenesis. The cell growth promoting effects of the Wnt and Notch pathways on hepatocytes and cholangiocytes, respectively, as well as their differential role on liver progenitor cells. The complicated dual role of TGF-β as guardian of cell cycle control, as well as its tumour promoting and invasion and metastasis inducing potential in all cell types is visualised. Finally, the complex interactions between these three pathways, and the possible influence of the HIF-1 pathway is presented.