Fig. 1

Summary of the evidence supporting the contribution of different cell lineages as CoO in HCC and iCCA. In a healthy liver, hepatic progenitor cells give rise to both cholangiocytes and hepatocytes. Cholangiocytes form bile ducts close to the portal vein (PV) and hepatic artery (HA), whereas hepatocytes constitute the bulk of liver mass and during their life cycle migrate towards the central vein (CV). Data from rodent models collected over the years suggest that any type of epithelial cell present in the liver (hepatocytes, cholangiocytes, and hepatic progenitor cells) can serve as CoO depending on the initiating event. Hepatocytes treated with chemical carcinogens, DEN, DEN/CCl₄ or TCPOBOP acquire mutations and undergo malignant transformation toward HCC. Similarly, transformation of cholangiocytes with TAA results in generation of iCCA. Hepatic progenitor cells may undergo malignant transformation following genetic events. BD bile duct; CCl₄ carbon tetrachloride, CV central vein, DEN Diethylnitrosamine, HA hepatic artery, PA portal vein, TAA thioacetamide, TCPOBOP 3,30,5,50-tetrachloro-1,4-bis(pyridyloxy)benzene