Document Detail


Cholangiocarcinomas can originate from hepatocytes in mice.
MedLine Citation:
PMID:  22797301     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-17
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-01     Completed Date:  2012-10-25     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2911-5     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Bile Duct Neoplasms / metabolism,  pathology*
Bile Ducts, Intrahepatic / metabolism,  pathology*
Cell Differentiation
Cell Lineage
Cholangiocarcinoma / etiology*,  metabolism,  pathology*
DNA Primers / genetics
Hepatocytes / metabolism,  pathology*
Humans
Liver Neoplasms / etiology*,  metabolism,  pathology*
Liver Neoplasms, Experimental / etiology,  metabolism,  pathology
Mice
Mice, Transgenic
Neoplastic Stem Cells / metabolism,  pathology
Proto-Oncogene Proteins c-akt / metabolism
Receptor, Notch1 / genetics,  metabolism
Receptors, Notch / metabolism
Recombinant Proteins / genetics,  metabolism
Signal Transduction
Grant Support
ID/Acronym/Agency:
P30 DK026743/DK/NIDDK NIH HHS; P30 DK026743/DK/NIDDK NIH HHS; R01 CA136606/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Notch1 protein, mouse; 0/Receptor, Notch1; 0/Receptors, Notch; 0/Recombinant Proteins; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections
Comment In:
Hepatology. 2013 Apr;57(4):1668-71   [PMID:  23390051 ]

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