Cholangiocarcinoma can originate from hepatocytes in mice

Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2012; 122(8):2911-5. DOI: 10.1172/JCI63212
Source: PubMed


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, Sep 30, 2015
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    • "Recommendation A1 • Further investigations regarding genetic polymorphisms and the risk of iCCA are recommended Suggestions for future studies Molecular pathogenesis Overview The molecular pathogenesis of iCCA is a complex issue involving several signal transduction pathways and molecular events (Fig. 2) [58] [59]. iCCA likely results from malignant transformation of cholangiocytes, and in a subset of cases from progenitor cells, although this paradigm has been challenged [1] [2]. Recent data "
    Journal of Hepatology 06/2014; 60(6). DOI:10.1016/j.jhep.2014.01.021
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    • "However, as with HPCs, there is no unique liver cancer progenitor cell marker specific to this cell population for the isolation of these cells and their consequent molecular and functional characterizations. On the other hand, recent investigations have shown that deregulation of Wnt signaling pathways can lead to the development of HCCs.69 Overexpression of Notch can result in the development of cholangiocarcinomas from hepatocytes which is similar to Notch activation in differentiation of HPCs toward cholangiocytes.70,71 Accurate, detailed double and triple immunostaing and confocal labeling is needed to clearly identify and label positive HPCs after which serial transplantation capability can be demonstrated in these cells,68 although the identification of specific gene products associated with HPCs or with HCCs remains challenging. "
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    ABSTRACT: The hepatic progenitor cell (HPC) niche is a special microenvironment composed of different cell types, extracellular matrix (ECM) components, growth factors and cytokines released by the niche cells that help to maintain the characteristics of HPCs and the balance between their activation, proliferation and differentiation. Composition of this special microenvironment, created in response to specific liver damage, together with critical interactions between different partners of the HPC niche can determine the fate decision and differentiation pathways of HPCs. A number of recent studies have shed light on factors and signals from the HPC niche that determines the choice of HPCs differentiation towards a specific cell type depending on the nature of the liver injury and resultant microenvironment created by this injury. This paper seeks to provide an in-depth review, through a literature review and the authors' experiences, of the most recent findings on the role of the HPC niche in fate choice option of HPCs toward either hepatocytes or bile duct epithelial cells and its clinical relevance.
    Middle East journal of digestive diseases 04/2014; 6(2):57-64.
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    • "A recent paper by Yanger et al. [37], adds further credit to the hypothesis that, depending on the type of liver injury, reactive cholangiocytes may actually be generated by a Notch-dependent reprogramming of hepatocytes. This is consistent with reports showing that intrahepatic cholangiocarcinoma (CCA) may also derive from hepatocytes [38] [39] (see below). "
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    ABSTRACT: Notch signaling is a crucial determinant of cell fate decision during development and disease in several organs. Notch effects are strictly dependent on the cellular context in which it is activated. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis. Recent advances have shed the light on Notch as a critical player in liver regeneration and repair, as well as in liver metabolism and inflammation and cancer. Notch signaling is finely regulated at several levels. The complexity of the pathway provides several possible targets for development of therapeutic agents able to inhibit Notch. Recent reports have shown that persistent activation of Notch signaling is associated with liver malignancies, particularly hepatocellular with stem cell features and cholangiocarcinoma. These novel findings suggest that interfering with the aberrant activation of Notch pathway may have therapeutic relevance. However, further studies are needed to clarify the mechanisms regulating physiologic and pathologic Notch activation in the adult liver, to better understand the mechanistic role(s) of Notch in liver diseases and to develop safe and specific therapeutic agents.
    Journal of Hepatology 12/2013; 60(4). DOI:10.1016/j.jhep.2013.11.028
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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

    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).

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