PMID- 22797301
OWN - NLM
STAT- MEDLINE
DCOM- 20121025
LR  - 20240507
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 122
IP  - 8
DP  - 2012 Aug
TI  - Cholangiocarcinomas can originate from hepatocytes in mice.
PG  - 2911-5
LID - 63212 [pii]
LID - 10.1172/JCI63212 [doi]
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.
FAU - Fan, Biao
AU  - Fan B
AD  - Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, 
      USA.
FAU - Malato, Yann
AU  - Malato Y
FAU - Calvisi, Diego F
AU  - Calvisi DF
FAU - Naqvi, Syed
AU  - Naqvi S
FAU - Razumilava, Nataliya
AU  - Razumilava N
FAU - Ribback, Silvia
AU  - Ribback S
FAU - Gores, Gregory J
AU  - Gores GJ
FAU - Dombrowski, Frank
AU  - Dombrowski F
FAU - Evert, Matthias
AU  - Evert M
FAU - Chen, Xin
AU  - Chen X
FAU - Willenbring, Holger
AU  - Willenbring H
LA  - eng
GR  - P30 DK026743/DK/NIDDK NIH HHS/United States
GR  - R01 CA136606/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120717
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (DNA Primers)
RN  - 0 (Notch1 protein, mouse)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptors, Notch)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
CIN - Hepatology. 2013 Apr;57(4):1668-71. PMID: 23390051
MH  - Animals
MH  - Base Sequence
MH  - Bile Duct Neoplasms/metabolism/*pathology
MH  - Bile Ducts, Intrahepatic/metabolism/*pathology
MH  - Cell Differentiation
MH  - Cell Lineage
MH  - Cholangiocarcinoma/*etiology/metabolism/*pathology
MH  - DNA Primers/genetics
MH  - Hepatocytes/metabolism/*pathology
MH  - Humans
MH  - Liver Neoplasms/*etiology/metabolism/*pathology
MH  - Liver Neoplasms, Experimental/etiology/metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplastic Stem Cells/metabolism/pathology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor, Notch1/genetics/metabolism
MH  - Receptors, Notch/metabolism
MH  - Recombinant Proteins/genetics/metabolism
MH  - Signal Transduction
PMC - PMC3408746
EDAT- 2012/07/17 06:00
MHDA- 2012/10/26 06:00
PMCR- 2012/07/17
CRDT- 2012/07/17 06:00
PHST- 2012/02/03 00:00 [received]
PHST- 2012/06/01 00:00 [accepted]
PHST- 2012/07/17 06:00 [entrez]
PHST- 2012/07/17 06:00 [pubmed]
PHST- 2012/10/26 06:00 [medline]
PHST- 2012/07/17 00:00 [pmc-release]
AID - 63212 [pii]
AID - 10.1172/JCI63212 [doi]
PST - ppublish
SO  - J Clin Invest. 2012 Aug;122(8):2911-5. doi: 10.1172/JCI63212. Epub 2012 Jul 17.