European Association for the Study of the Liver (EASL), Berlin, Germany, 30 March 2012 - 03 April 2011
Throughout the last decade 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.
Here we show that expression of the intracellular domain of the Notch receptor in transgenic mice leads to the formation of intrahepatic CCC in all animals. These tumors form highly aggressive carcinomas after transplantation into nude mice. Notch overexpressing hepatocytes show a proliferation defect and
transition from mitosis to endoreduplication cycles. This transition is initiated by cyclin E expression. For the first time we were able to show that Notch directly regulates the cyclin E promotor. So we identify the cyclin E gene as a transcriptional target of the Notch signaling pathway in cell lines derived from CCC and detect high levels of cyclin E in primary CCC tissues.
Moreover 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 find the Notch 1 and 3 receptors to be strongly expressed in human tumor tissue as compared to normal liver.
Inhibition of Notch signaling in CCC cell lines in vitro or in xenotransplanted tumors in vivo using g- secretase inhibitors results in an induction of the cyclin kinase inhibitors p21 and p53 and an amelioration of cell proliferation as well as the induction of apoptosis.
Together these results show that aberrant Notch signalling leads to a dysregulation of the oncogene cyclin E which then leads to the formation of CCC and that pharmacological interference with this pathway blocks the growth of these tumors and might constitute a new treatment option.