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

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Ikenoue Tsuneo 東京大学, 医科学研究所, 准教授 (80396712)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 肝内胆管癌 / マウスモデル / 起源細胞 / Kras / Pten / Notchシグナル

Outline of Final Research Achievements

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 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.

Free Research Field

消化器病学