Article

Cholangiocarcinomas can originate from hepatocytes in mice.

Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, USA.
The Journal of clinical investigation (Impact Factor: 13.77). 07/2012; 122(8):2911-5. DOI: 10.1172/JCI63212
Source: PubMed

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.

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Available from: Diego F Calvisi, Jun 30, 2015
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Questions & Answers about this publication

  • Go J Yoshida added an answer in Cholangiocarcinoma:
    What are the causes of a hepatic cholangiocarcinoma?

    Can they be of a congenital nature?

    The hepatic cholangiocarcinoma is one of the form of extremely rare cancer and most dangerous, however I would like to know the precise causes and especially if this pathology is related to a transmissible gene.

    Go J Yoshida · Tokyo Medical and Dental University

    As you mentioned, cholangiocellular carcinoma (CCC) is rare but increasing worldwide.

    Liver tissue is composed of several types of cells and importantly, hepatocytes and cholangiocyes have the identical progenitor cells. That is why TGF-beta signal-induced inflammation and fibrosis and  alcoholic cirrhosis or NASH in the clinical settings would promote not only hepatic cell-derived cancer (HCC) but also cholangiocellular carcinoma (CCC). Indeed, according to the pathological classifications of the heaptic tumors, not a few patients develop the mixed type of HCC and CCC with significant fibrosis.

       In the perspective from genetic alterations,  tissue-specific disruption of the tumor suppressor genes such as  NF2, SMAD4 andPTEN contributes to the development of CCC. Furthermore, It has been recently reported that hyper-activation of the Notch signaling pathway leads to a dysregulation of the oncogenic cyclinE and subsequent genetic instability, which results in the incidence of CCC. Inhibition of Notch intra-cellular domain (NICD) activity in CCC blocks tumor cell proliferation and induces apoptosis in vitro and in vivo; loss of Notch 1 expression led to a reduction in HES1 and cyclin E expression, while p53, p27, and p21 were strongly induced and cell-cycle would be arrested (apoptosis or senescence).