A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas

The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic proge...

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Bibliographic Details
Published in:	Cancer cell Vol. 23; no. 6; pp. 784 - 795
Main Authors:	Zender, Steffen, Nickeleit, Irina, Wuestefeld, Torsten, Sörensen, Inga, Dauch, Daniel, Bozko, Przemyslaw, El-Khatib, Mona, Geffers, Robert, Bektas, Hueseyin, Manns, Michael P., Gossler, Achim, Wilkens, Ludwig, Plentz, Ruben, Zender, Lars, Malek, Nisar P.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-06-2013
Subjects:	Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Apoptosis - genetics Cell Proliferation Cholangiocarcinoma - genetics Cholangiocarcinoma - pathology Cyclin E - genetics Cyclin E - metabolism Down-Regulation Gene Expression Regulation, Neoplastic Hepatocytes - cytology Humans Liver - metabolism Mice Mice, Transgenic Receptor, Notch1 - chemistry Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Signal Transduction Transplantation, Heterologous
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Summary:	The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic progenitor cells, indicating that intrahepatic CCC can originate from this cell type. We show that human and mouse CCCs are characterized by high expression of the cyclin E protein and identified the cyclin E gene as a direct transcriptional target of the Notch signaling pathway. Intriguingly, blocking γ-secretase activity in human CCC xenotransplants results in downregulation of cyclin E expression, induction of apoptosis, and tumor remission in vivo. •Notch signaling is frequently dysregulated in human CCCs•Notch is an oncogenic driver of CCC and able to transform hepatic progenitor cells•Notch induces the cyclin E promoter, causing genetic instability by increasing cyclin E expression•Inhibition of Notch signaling may be a treatment option for CCC
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1535-6108 1878-3686
DOI:	10.1016/j.ccr.2013.04.019