J Clin Invest.：胆管癌可起源于肝细胞

7月16日，J Clin Invest.杂志在线报道胆管癌在小鼠模型中可起源于肝细胞。研究者认为，这一发现加深了人类对肝内胆管癌起源的认识，可为开发更有针对性的治疗方法打下基础。

肝内胆管癌（ICCs）是预后较差的原发性肝肿瘤。由于对其生物学特性不够了解，一直难以找到有效的治疗方法。虽然ICCs在位置，组织学和标志物表达等方面表现出异质性，它们目前总是被认为起源于沿胆管排列的细胞，胆管上皮细胞（BECs），或肝脏祖细胞（LPCs）。

尽管缺乏实验证据确认BECs或LPCs作为ICCs的起源，其他肝细胞类型都没有被考虑。本研究表明，ICCs可以源于完全分化的肝细胞。

利用小鼠模型进行肝细胞命运追踪，研究者发现，激活的Notch和AKT信号协同促进正常肝细胞转换成胆管细胞。后者成为进展迅速，致命性的ICCs的前体细胞。

研究结果表明，以前被忽视了人类的ICCs形成机制，可能成为靶向性治疗ICCs的新的有效靶点。

doi:10.1016/j.cell.2011.10.017
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Cholangiocarcinomas can originate from hepatocytes in mice

Biao Fan1,2, Yann Malato3,4, Diego F. Calvisi5, Syed Naqvi3, Nataliya Razumilava6, Silvia Ribback5, Gregory J. Gores6, Frank Dombrowski5, Matthias Evert5, Xin Chen1,7 and Holger Willenbring

Intrahepatic cholangiocarcinomas (ICCs) are primary liver tumors with a poor prognosis. The development of effective therapies has been hampered by a limited understanding of the biology of ICCs. Although ICCs exhibit heterogeneity in location, histology, and marker expression, they are currently thought to derive invariably from the cells lining the bile ducts, biliary epithelial cells (BECs), or liver progenitor cells (LPCs). Despite lack of experimental evidence establishing BECs or LPCs as the origin of ICCs, other liver cell types have not been considered. Here we show that ICCs can originate from fully differentiated hepatocytes. Using a mouse model of hepatocyte fate tracing, we found that activated NOTCH and AKT signaling cooperate to convert normal hepatocytes into biliary cells that act as precursors of rapidly progressing, lethal ICCs. Our findings suggest a previously overlooked mechanism of human ICC formation that may be targetable for anti-ICC therapy.