Epithelial plasticity of hepatocytes during liver tumor progression

Hepatocellular carcinoma (HCC) correlates with poor survival of patients due to delayed diagnosis and frequent recurrence after adjuvant treatment. The majority of malignant hepatic lesions shows a tremendous heterogeneity in differentiation patterns and molecular signatures which challenges efficient therapeutic intervention. Here we discuss aspects on which route hepatocytes progress towards epithelial lineage commitment during liver repopulation and further resume configurations of hepatocyte differentiation during liver tumorigenesis. We particularly focus on the epithelial to mesenchymal transition (EMT) of hepatocytes and its consequences upon the progression of HCC which depends on the synergy of transforming growth factor (TGF)-β signaling and the hyperactivation of Ras-subeffectors. Recent insights into the epithelial plasticity of malignant hepatocytes revealed that activation of platelet-derived growth factor (PDGF) links TGF-β signaling to nuclear β-catenin accumulation upon EMT. PDGF-dependent activation of β- catenin reduces cellular turnover and provides protection of malignant hepatocytes against anoikis, the latter known as a prerequisite for dissemination of carcinoma and a feature of metastatic cancer stem cells. Finally, we discuss the cancer cell fate determination by integrating the repertoire of hepatocellular differentiation in a novel concept of liver carcinoma progression. © 2008 Springer.