Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma.
Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma.
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DOI：
10.1158/0008-5472.can-11-3596
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发表时间：
2012-03-15
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：
O'Dell MR;Huang JL;Whitney-Miller CL;Deshpande V;Rothberg P;Grose V;Rossi RM;Zhu AX;Land H;Bardeesy N;Hezel AF
肝内胆管癌（IHCC）是一种原发性肝癌，发病率上升，预后差。这种疾病的病因和治疗的临床前研究受到可用的IHCC细胞系或遗传可靠的动物模型数量相对较少的阻碍。在这里，我们报道了一种IHCC基因工程小鼠模型的发展，该模型包含了人类IHCC中最常见的两种突变，即Kras的激活突变（KrasG12D）和p53的缺失。KrasG12D的组织特异性激活导致侵袭性IHCC的发展，具有低外显率和长潜伏期。通过将KrasG12D激活与p53杂合或纯合缺失相结合，缩短了潜伏期（平均生存期分别为56周和19周），这也导致了广泛的局部和远处转移。系列分析表明，小鼠模型密切再现了人类疾病的多阶段组织病理学进展，包括富间质肿瘤的发展和胆道癌前病变、导管内乳头状胆道肿瘤（IPBN）和Von Meyenburg复合体（VMC，也称为胆道错构瘤）。这些发现建立了一个新的遗传和组织病理学上可靠的IHCC模型，并为IPBN和VMC是侵袭性癌症前体的假设提供了实验支持。
Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (KrasG12D) and deletion of p53. Tissue-specific activation of KrasG12D alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining KrasG12D activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks versus 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the pre-malignant biliary lesions, intraductal papillary biliary neoplasms (IPBN) and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers.