title: A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion.
abstract: 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.
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Terakado
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.affiliation: Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Diagnostic Pathology, Jichi Medical University, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsubara
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Noguchi
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Asaoka
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Department of Diagnostic Pathology, Jichi Medical University, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Fukushima
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Yokohama City University, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018281:Cholangiocarcinoma / Q000209:etiology* / Q000235:genetics; D003433:Crosses, Genetic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D022781:Hepatocytes; D006965:Hyperplasia; D019426:Integrases; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse