Modeling Pathogenesis of Primary Liver Cancer in Lineage Specific Cell Types

Classification of human liver cancer into biologically distinct subgroups suggests origin from different hepatic lineage cells. To clarify contribution of lineage stage in liver oncogenesis, we transduced H-Ras and SV40LT into hepatic progenitor cells (HPC), hepatoblasts (HB) and terminally differentiated adult hepatocytes (AH). Regardless of origin, all transformed cell types acquired common cancer stem cell characteristics in vitro and in vivo. However, expression analysis distinguished tumors of different cellular origin underscoring the contribution of lineage/stage-dependent genetic changes in malignant transformation. Notably, AH-derived tumors showed specific enrichment of c-Myc target genes. These data establish that any hepatic lineage cell can be a target for transformation and acquire common cancer stem cell traits via activation of diverse cell type specific pathways. Profiling of individual tumors derived by Ras/SV40 transformation of hepatic progenitor cell (oval cells), hepatoblasts (fetal) and adult hepatocytes