Cancer Stem Cell Model for HCC Tumorigenesis. The generation of a CSC model will more effectively benefit the clinical treatment of HCC patients, allowing therapy directed at the most aggressive cells. So far, there is no compelling data demonstrating that HCC follows this model. To test the CSC model, at least two terms have to be addressed: 1) The vast majority of HCC cells, excluding the small subpopulation of CSCs, lack tumorigenic capacity; 2) These CSC populations are distinguished by epigenetic rather than genetic differences because the CSC model argues that CSCs undergo hierarchical differentiation and the epigenetic changes are irreversible. Two HCC subgroups were recently identified based on the expression of AFP and EpCAM. EpCAM+AFP+ HCC subgroup (HpSC-HCC) had the features of hepatic stem/progenitor cells and EpCAM-AFP- HCC subgroup (MH-HCC) featured as matured hepacytes. HpSC-HCC displayed the ability to self-renew, differentiate and also generate highly invasive HCC. Based on these observations, it is plausible that HCC may represent another solid cancer type that follows the CSC model besides breast, brain and colon cancers. Consistent with the clonal evolution model, HCC CSCs can arise from the mutation of normal hepatic stem/progenitor cells. Though there has not been evidence showing that HCC CSCs can arise from differentiated hepatocytes, the possibility still exits, as there are examples of this in hematopoietic malignancies. Overall, not in contrast to the clonal evolution model, an accumulation of mutations during the normal development of hepatocytes as a consequence of exposure to the various risk factors of HCC might contribute to the rise of the hepatic CSCs; therefore the two models do not contrast but complement each other.