Abstract 658: Elucidation of cellular origin of mouse intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

Abstract

Abstract Regarding the carcinogenesis of intrahepatic cholangiocarcinoma (ICC), growing interest has been focused on its cellular origin, namely cholangiocytes, progenitor cells, or hepatocytes. We have recently established a novel mouse model of ICC by introducing liver-specific Kras activation and Pten deletion using Alb-Cre mice, in which Cre/loxP-mediated gene recombination was achieved in hepatoblasts and mature hepatocytes. To elucidate the cellular origin of ICC in this mouse model, we utilized hepatocyte or cholangiocyte-lineage specific gene engineering using a tamoxifen (TMX) inducible-Cre/loxP system. The mice carrying Kras activation and Pten deletion by Alb-CreERT2 mice with the TMX treatment at eight weeks of age developed hepatocellular carcinoma and hepatocyte dysplasia within three months. Fluorescence microscopy analyses disclosed that the Cre/loxP-mediated gene recombination was specifically observed in hepatocytes in the mice. In contrast, the mice carrying Kras activation and Pten deletion by Alb-CreERT2 mice at ten days of age induced ICC alone within two months. The gene recombination occurred in cholangiocytes as well as hepatocytes. Expectedly, ICCs were developed in the mice carrying cholangiocyte-specific Kras activation and Pten deletion by K19CreERT mice treated with TMX at 8 weeks after birth. TMX-induced, Cre/loxP-mediated recombination was achieved in epithelia of various organs including intrahepatic bile ducts in these mice. These results suggest that the cellular origin of ICC in mice carrying liver-specific Kras activation and Pten deletion was cholangiocytes but not hepatocytes. This mouse model should be useful for better understanding of human ICC of cholangiocyte-origin and the development of new therapeutic strategies for the disease. Citation Format: Tsuneo Ikenoue, Yumi Terakado, Kiyoshi Yamaguchi, Yoichi Furukawa. Elucidation of cellular origin of mouse intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 658.