title: A critical role for notch signaling in the formation of cholangiocellular carcinomas.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Zender
authors.forename: Irina
authors.initials: I
authors.lastname: Nickeleit
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Inga
authors.initials: I
authors.lastname: Sörensen
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.forename: Mona
authors.initials: M
authors.lastname: El-Khatib
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Hueseyin
authors.initials: H
authors.lastname: Bektas
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Achim
authors.initials: A
authors.lastname: Gossler
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.forename: Ruben
authors.initials: R
authors.lastname: Plentz
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D019927:Cyclin E; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases