Z Gastroenterol 2010; 48 - V56
DOI: 10.1055/s-0030-1263410

Activation of the Notch signaling pathway is involved in the formation of cholangiocellular carcinomas

S Zender 1, 2, I Nickeleit 2, R Geffers 3, S Chauhan 2, S Kubicka 1, H Bektas 4, R Plentz 1, A Gossler 2, L Wilkens 5, MP Manns 1, NP Malek 1, 2
  • 1Medizinische Hochschule Hannover, Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
  • 2Medizinische Hochschule Hannover, Institut für Molekularbiologie, Hannover, Germany
  • 3Helmholtz-Zentrum für Infektionsforschung, Zellbiologie, Array Facility, Braunschweig, Germany
  • 4Medizinische Hochschule Hannover, Klinik für Allgemein-, Visceral- und Transplantationschirurgie, Hannover, Germany
  • 5Nordstadtkrankenhaus Hannover, Institut für Pathologie, Hannover, Germany

Throughout the last years the incidence of cholangiocellular carcinoma (CCC) in western european countries and the US is constantly rising. The pathogenesis of this devastating disease is however not well understood.

Previously it was shown that the Notch signaling pathway is crucial for the development of the biliary system as loss of the Notch ligand Jagged results in hypoplasia of the biliary system (Alagille syndrome).

Here we show that expression of the intracellular domain of the notch 1 receptor in transgenic mice leads to the formation of intrahepatic CCC. These tumors form highly aggressive carcinomas after transplantation into nude mice. Moreover, we found that the notch signaling pathway is constitutively activated in established human CCC cell lines and in primary cell lines derived from human CCC. Analyzing a large panel of human CCC we found the Notch 1 and 3 receptors to be strongly expressed in human tumor tissue as compared to normal liver.

In our mouse model we were able to show that at the age of 10 weeks mature hepatocytes appeared atrophic and showed enlarged nuclei and an increased nuclear-cytoplasmic ratio.

Consistent with previous data from drosophila we found that constitutive expression of Notch-ICD leads to the induction of endoreduplication cycles and an increase in the expression of the APC subunit cdh1 and of cyclin E. Interestingly, at the age of 8 months Notch-ICD transgenic develop undifferentiated intrahepatic tumors which display features of human cholangiocellular carcinomas.

Inhibition of Notch signaling in CCC cell lines in vitro or in xenotransplanted tumors in vivo results in an induction of the cyclin kinase inhibitor p21 and an amelioration of cell proliferation as well as the induction of apoptosis.

Together these results show that constitutive notch signaling can lead to the formation of CCC and that pharmacological interference with this pathway blocks the growth of these tumors.