Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma.
Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma.
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DOI：
10.1158/0008-5472.can-17-1123
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发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Hezel AF
中科院分区：
文献类型：
--
作者：
Hill MA;Alexander WB;Guo B;Kato Y;Patra K;O'Dell MR;McCall MN;Whitney-Miller CL;Bardeesy N;Hezel AF
肝内胆管细胞癌(ICCA)是一种流行病学上与肝损伤相关的原发性肝癌，其早期阶段知之甚少，缺乏早期诊断和有效治疗。虽然ICCA通常被认为起源于胆道，但研究表明，肝细胞和胆管细胞(胆管细胞)都可能引起ICCA。与这些细胞系的可塑性一致，原发性肝癌表现出从肝细胞癌(HCC)到iCCA的表型范围，中间产物沿着这一谱。在这里，我们建立了小鼠模型，以检查靶向突变Kras和TP53的后果，这两个突变是人类iCCA中常见的变化，作用于不同类型的成人肝细胞。在SOX9+人群中选择性地诱导这些突变，主要是成熟的胆管细胞，导致了来自癌前胆管上皮内瘤变(BillN)的iCCA。相比之下，成人肝细胞对这些突变相对耐药，并形成罕见的肝细胞癌(HCC)。在这种背景下，损伤加速了肝细胞来源的肿瘤的发生，并促进了表型向iCCA的转变。在肝细胞来源的iCCA模型中没有胆碱前体病变，这表明损伤的、致癌的肝细胞直接出现了恶性胆管细胞表型。TP53缺失促进了肝细胞向胆管细胞的重编程，这可能是促进肝细胞源性iCCA形成的机制之一。总体而言，我们的工作表明，Kras和TP53驱动的iCCA可能来自成熟的胆管细胞和肝细胞，慢性肝损伤和潜在的基因突变等因素决定了进展路径和导致的癌症表型。
Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA with intermediates along this spectrum. Here we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BillN). By contrast, adult hepatocytes were relatively refractory to these mutations and formed rare hepatocellular carcinomas (HCC). In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing towards distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced reprogramming of hepatocytes to biliary cells, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.