Fig. 12.

Proposed “retrodifferentiation model” for HCV-induced liver carcinogenesis. Solid arrows, pathways of normal hepatic stem cell differentiation; arrows with broken lines, possible sources of Huh7.5- and GS5-derived tumors. The majority of Huh7.5 culture/tumor cells lack or show very low levels of hepatic/biliary precursor markers. Therefore, they represent intermediate or differentiated hepatocytes. On the other hand, GS5 culture/tumor cells contain stem cell/progenitor cell markers and high populations of CK19⁺ AFP⁻ (hepatic stem cells) and CK19⁺ AFP⁺ (hepatoblasts, transit-amplifying cells, or hepatic/biliary precursors) cells. The expression levels of DCAMKL-1, CK19, and AFP in these cells are remarkably higher than those in Huh7.5 cells. These acquired distinctions can probably be attributed to retrodifferentiation of the parent Huh7.5 cells into the GS5 phenotype that was induced by sustained expression of the HCV replicon. HCC, hepatocellular carcinoma; HPC, hepatic progenitor cell.