Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
J Clin Invest. 2012 Nov;122(11):3914-8. doi: 10.1172/JCI63065.
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.
肝内胆管癌 (ICC) 是肝脏的第二大常见原发性恶性肿瘤。ICC 被归类为源自胆管细胞的恶性肿瘤;然而，ICC 与病毒性肝炎的同时发生表明 ICC 起源于肝细胞。为了确定 ICC 的细胞起源，我们使用了一种 ICC 的小鼠模型，其中肝细胞和胆管细胞被可遗传的、细胞类型特异性的报告基因标记。我们的研究表明，ICC 是由源自肝细胞的胆管细胞谱系细胞产生的，而不是胆管细胞。此外，我们发现 Notch 激活对于 ICC 发生及其随后的恶性转化和进展过程中肝细胞向胆管细胞谱系细胞的转化至关重要。这些发现将有助于阐明 ICC 的发病机制，并为这种难治性疾病开发治疗策略。
