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Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific  Kras  activation and  Pten  deletion. An activating mutation of  Kras  in combination with deletion of  Pten  was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre- loxP  system. As a result, liver-specific  Kras  activation and homozygous  Pten  deletion cooperated to induce ICCs exclusively. In contrast,  Kras  activation in combination with heterozygous  Pten  deletion induced both ICCs and HCCs, whereas  Kras  activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre- loxP  demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific  Kras  activation in combination with homozygous  Pten  deletion should be useful for the investigation of therapeutic strategies for human ICC.

A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion