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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Bile Duct Neoplasms / metabolism
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Bile Duct Neoplasms / pathology*
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Bile Ducts, Intrahepatic / metabolism
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Bile Ducts, Intrahepatic / pathology*
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Cell Differentiation
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Cell Lineage
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Cholangiocarcinoma / etiology*
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Cholangiocarcinoma / metabolism
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Cholangiocarcinoma / pathology*
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DNA Primers / genetics
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Hepatocytes / metabolism
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Hepatocytes / pathology*
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Humans
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Liver Neoplasms / etiology*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Liver Neoplasms, Experimental / etiology
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism
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Receptors, Notch / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
Substances
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DNA Primers
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Notch1 protein, mouse
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Receptor, Notch1
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Receptors, Notch
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Recombinant Proteins
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Proto-Oncogene Proteins c-akt