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Cholangiocarcinomas can originate from hepatocytes in mice
Biao Fan, … , Xin Chen, Holger Willenbring
Biao Fan, … , Xin Chen, Holger Willenbring
Published July 17, 2012
Citation Information: J Clin Invest. 2012;122(8):2911-2915. https://doi.org/10.1172/JCI63212.
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Brief Report

Cholangiocarcinomas can originate from hepatocytes in mice

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Abstract

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.

Authors

Biao Fan, Yann Malato, Diego F. Calvisi, Syed Naqvi, Nataliya Razumilava, Silvia Ribback, Gregory J. Gores, Frank Dombrowski, Matthias Evert, Xin Chen, Holger Willenbring

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Figure 1

NICD/AKT-induced ICC formation.

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NICD/AKT-induced ICC formation.
(A) Photographic images of mouse livers ...
(A) Photographic images of mouse livers taken at different time points after NICD/AKT plasmid injection. Small tumors (arrows) were visible as early as 3.5 weeks after injection. (B) H&E stainings of corresponding liver sections show rapidly expanding tumors replacing the normal liver parenchyma. Original magnification, ×40. At least 15 liver sections from 3 mice were analyzed for each time point.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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