Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested it can also arise from fetal progenitor cells or their adult progenitor progeny. Here we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreER™-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER™) and GFP are controlled by a 190kb 5′ genomic region of Cited1, a transcriptional co-activator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreER™-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes and SOX9+ periductal cells. By 26 weeks of age, >90% of Cited1-CreER™-GFP; Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas (HB) and lung metastases. HCC and HB resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK and PI3K/AKT/mTOR pathways, and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and HB and the development of improved therapeutics for these diseases.

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<p>PDF file - 1419KB, Characterization of CreERTM-GFP+ cells of fetal liver.</p>

<p>PDF file - 868KB, Activation of MAPK and mTOR pathways in HCCs.</p>