7月16日,，J Clin Invest.雜志在線報(bào)道膽管癌在小鼠模型中可起源于肝細(xì)胞。研究者認(rèn)為,，這一發(fā)現(xiàn)加深了人類對肝內(nèi)膽管癌起源的認(rèn)識，可為開發(fā)更有針對性的治療方法打下基礎(chǔ)。
肝內(nèi)膽管癌（ICCs）是預(yù)后較差的原發(fā)性肝腫瘤,。由于對其生物學(xué)特性不夠了解，一直難以找到有效的治療方法,。雖然ICCs在位置,，組織學(xué)和標(biāo)志物表達(dá)等方面表現(xiàn)出異質(zhì)性，它們目前總是被認(rèn)為起源于沿膽管排列的細(xì)胞，膽管上皮細(xì)胞（BECs）,，或肝臟祖細(xì)胞（LPCs）,。
盡管缺乏實(shí)驗(yàn)證據(jù)確認(rèn)BECs或LPCs作為ICCs的起源，其他肝細(xì)胞類型都沒有被考慮,。本研究表明,，ICCs可以源于完全分化的肝細(xì)胞。
利用小鼠模型進(jìn)行肝細(xì)胞命運(yùn)追蹤,，研究者發(fā)現(xiàn),，激活的Notch和AKT信號協(xié)同促進(jìn)正常肝細(xì)胞轉(zhuǎn)換成膽管細(xì)胞。后者成為進(jìn)展迅速,，致命性的ICCs的前體細(xì)胞,。
研究結(jié)果表明，以前被忽視了人類的ICCs形成機(jī)制,，可能成為靶向性治療ICCs的新的有效靶點(diǎn),。(生物谷bioon.com)
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.
