Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes
Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes
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DOI：
10.1172/jci63065
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Suzuki, Atsushi
中科院分区：
文献类型：
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作者：
Sekiya, Sayaka;Suzuki, Atsushi
肝内胆管细胞癌(ICC)是肝脏第二常见的原发恶性肿瘤。ICC已被归类为起源于胆管细胞的恶性肿瘤；然而，ICC与病毒性肝炎的并存表明ICC起源于肝细胞。为了确定ICC的细胞来源，我们使用了一种ICC的小鼠模型，在该模型中，肝细胞和胆管细胞被可遗传的、细胞类型特异性的报告分子标记。我们的研究表明，ICC是由来自肝细胞的胆系细胞产生的，而不是来自胆管细胞。此外，我们还发现，在ICC的发病过程中，Notch的激活对于肝细胞转化为胆系细胞以及随后的恶变和进展是至关重要的。这些发现将有助于阐明ICC的发病机制，并为这一难治性疾病制定治疗策略。
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy in the liver. ICC has been classified as a malignant tumor arising from cholangiocytes; however, the co-occurrence of ICC and viral hepatitis suggests that ICC originates in hepatocytes. In order to determine the cellular origin of ICC, we used a mouse model of ICC in which hepatocytes and cholangiocytes were labeled with heritable, cell type-specific reporters. Our studies reveal that ICC is generated by biliary lineage cells derived from hepatocytes, rather than cholangiocytes. Additionally, we found that Notch activation is critical for hepatocyte conversion into biliary lineage cells during the onset of ICC and its subsequent malignancy and progression. These findings will help to elucidate the pathogenic mechanism of ICC and to develop therapeutic strategies for this refractory disease.