A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion.
A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion.
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DOI：
10.1038/srep23899
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发表时间：
2016-04-01
影响因子：
4.6
通讯作者：
Furukawa Y
中科院分区：
文献类型：
--
作者：
Ikenoue T;Terakado Y;Nakagawa H;Hikiba Y;Fujii T;Matsubara D;Noguchi R;Zhu C;Yamamoto K;Kudo Y;Asaoka Y;Yamaguchi K;Ijichi H;Tateishi K;Fukushima N;Maeda S;Koike K;Furukawa Y
肝内胆管细胞癌（Intrahepatic cholangiocarcinoma，ICC）是一种侵袭性强、预后差的恶性肿瘤，其发病率在世界范围内呈上升趋势.最近，几种类型的细胞已被认为是ICC的起源，即胆管细胞，肝祖细胞和肝细胞。在这里，我们已经建立了一个新的小鼠ICC模型，通过肝脏特异性Kras激活和Pten缺失。使用Cre-loxP系统将Kras的激活突变与Pten的缺失组合引入胚胎肝双能祖细胞（所谓的成肝细胞）和成熟肝细胞中。因此，肝脏特异性Kras激活和纯合Pten缺失合作，诱导ICC排他。相反，Kras激活与杂合Pten缺失相结合诱导ICC和HCC，而Kras激活单独导致HCC而不是ICC。此外，使用他莫昔芬诱导的Cre-loxP的细胞谱系可视化系统表明，ICC不起源于肝细胞，但来自胆管细胞。我们的数据表明，携带肝脏特异性Kras激活与纯合Pten缺失相结合的小鼠应有助于研究人类ICC的治疗策略。
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.