Z Gastroenterol 2012; 50 - K103
DOI: 10.1055/s-0032-1324038

The Hedgehog signalling pathway: A novel therapeutic target for cholangiocellular carcinoma

M El Khatib 1, A Kalnytska 2, V Palagani 1, U Kossatz 1, M Manns 2, L Wilkens 3, N Malek 1, R Plentz 1
  • 1Medizinische Universitätsklinik Tübingen, Gastroenterologie, Hepatologie und Infektiologie, Tübingen, Germany
  • 2Medizinische Hochschule Hannover, Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
  • 3Nordstadt Krankenhaus, Pathologie, Hannover, Germany

Introduction: The Hedgehog (Hh) signalling pathway is an important developmental pathway that is aberrant in many cancers. However, the role of this signalling pathway in the carcinogenesis of Cholangiocarcinoma (CCC) is still unknown.

Aims: Here, we investigated the effects of Hh inhibition by Cyclopamine in vivo using a Xenograft mouse model and in cultured human CCC cell lines.

Methods: We analyzed the effect of Cyclopamine on Xenograft tumors and the involvement of Hh in cell proliferation, epithelial to mesenchymal transition (EMT), migration and invasion.

Results: Sonic hedgehog (SHH) ligand was highly expressed in 89% of primary human CCC specimens (n=40) and in human CCC cell lines. Cyclopamine treatment effectively blocked CCC cell proliferation, migration and invasion by down-regulating Hh target genes, glioblastoma 1 (Gli1) and glioblastoma 2 (Gli2). In addition, Hh inhibition caused an increase of the epithelial marker, E-cadherin. Importantly, we were able to prove the ability of cyclopamine to significantly inhibit the growth CCC xenograft tumors.

Conclusion: Our study highlights the importance of Hh pathway in the carcinogenesis of CCC and suggests that down-regulation of Hh by Cyclopamine may be an effective strategy for treatment of human CCC.