Mouse model of CCl4-induced HCC: histopathological changes and expression of EGF and CD133

2954 Background: Repeated exposure to carbon tetrachloride (CCl4) has historically been used as a model of chronic liver injury leading to cirrhosis and hepatocellular carcinoma (HCC) in rodents. Chronic liver injury leads to hepatic stellate cell (HSC) proliferation and differentiation and consequent deposition of extracellular matrix proteins like collagen resulting in fibrosis and cirrhosis. A novel subpopulation of HSCs, which express CD133 and exhibit properties of progenitor cells, has recently been described in rats. In the setting of chronic human liver injury, epidermal growth factor (EGF) and EGF receptor (EGFR) have been proposed to have vital roles in liver regeneration and tumor progression. Methods: Strain A/J male mice were treated 3X a week for 17 weeks by oral gavage with either 0.04 cc of a 40% solution of CCl4 in olive oil or vehicle. Pathological examination of the livers was performed with Masson9s trichrome and HE however, no evidence of cirrhosis was present. Consistent with this, increased expression of desmin and GFAP, known to be representative markers of HSCs, was observed. Interestingly, CD133 was dramatically up-regulated after treatment with CCl4 and was attributed to HSCs as the expression of VEGFR2, a marker for endothelial progenitor cells, was not altered. Further, upon withdrawal of CCl4, the expression of CD133 returned to control levels in the surrounding normal tissue but remained elevated in the tumor. Finally, EGF and EGFR expression significantly decreased during chronic liver injury, but returned to nearly control levels during liver repair after withdrawal of CCl4. Conclusions: The use of CCl4-induced chronic liver injury in mice may not be an adequate model of human cirrhosis. In this study, no evidence of cirrhosis was seen and HCCs developed within a setting of fibrosis and not cirrhosis as typically observed in humans. Further, EGF and EGFR expression decreased during chronic liver injury. These results suggest that species-specific differences exist with respect to the histopathological and molecular pathogenesis of chronic liver disease. The dramatic up-regulation of CD133 is a notable finding and the contribution of CD133+ HSC to liver regeneration and tumor progression await further studies in rodents and humans.