TY - JOUR
T1 - Cholangiocarcinomas can originate from hepatocytes in mice
AU - Fan, Biao
AU - Malato, Yann
AU - Calvisi, Diego F.
AU - Naqvi, Syed
AU - Razumilava, Nataliya
AU - Ribback, Silvia
AU - Gores, Gregory J.
AU - Dombrowski, Frank
AU - Evert, Matthias
AU - Chen, Xin
AU - Willenbring, Holger
PY - 2012/8/1
Y1 - 2012/8/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI63212
DO - 10.1172/JCI63212
M3 - Article
C2 - 22797301
AN - SCOPUS:84864773126
SN - 0021-9738
VL - 122
SP - 2911
EP - 2915
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -