Hedgehog pathway as a potential treatment target in human cholangiocarcinoma

J Hepatobiliary Pancreat Sci. 2014 Aug;21(8):607-15. doi: 10.1002/jhbp.107. Epub 2014 Apr 15.


Background: Innovative treatment concepts targeting essential signaling pathways may offer new chances for patients suffering from cholangiocarcinoma (CCC). For that, we performed a systematic molecular genetic analysis concerning the Hedgehog activity in human CCC samples and analyzed the effect of Hh inhibition on CCC cells in vitro and in vivo.

Methods: Activation of the Hh pathway was analyzed in 50 human CCC samples using quantitative polymerase chain reaction (qPCR). The efficacy of Hh inhibition using cyclopamine and BMS-833923 was evaluated in vitro. In addition, the effect of BMS-833923, alone or in combination with gemcitabine, was analyzed in vivo in a murine subcutaneous xenograft model.

Results: Expression analysis revealed a significant activation of the Hh-signaling pathway in nearly 50% of CCCs. Hh inhibition resulted in a significant decrease in cell proliferation of CCC cells. Moreover, a distinct inhibition of tumor growth could be seen as a result of a combined therapy with BMS-833923 and gemcitabine in CCC xenografts.

Conclusion: The results of our study suggest that the Hh pathway plays a relevant role at least in a subset of human CCC. Inhibition of this pathway may represent a possible treatment option for CCC patients in which the Hh pathway is activated.

Keywords: Cholangiocarcinoma; Gemcitabine; Hedgehog proteins; Molecular targeted therapy; Sonic Hedgehog inhibitor.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Benzamides / administration & dosage
  • Benzamides / pharmacology
  • Bile Duct Neoplasms / drug therapy*
  • Bile Ducts, Intrahepatic*
  • Cells, Cultured
  • Cholangiocarcinoma / drug therapy*
  • Female
  • Gene Expression
  • Gentamicins / administration & dosage
  • Gentamicins / pharmacology
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Transplantation
  • Oncogene Proteins / genetics
  • Patched Receptors
  • Polymerase Chain Reaction
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology
  • RNA, Messenger / analysis
  • Receptors, Cell Surface / genetics
  • Signal Transduction / drug effects
  • Trans-Activators / genetics
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein GLI1


  • BMS-833923
  • Benzamides
  • Gentamicins
  • Hedgehog Proteins
  • Oncogene Proteins
  • Patched Receptors
  • Quinazolines
  • RNA, Messenger
  • Receptors, Cell Surface
  • SHH protein, human
  • Trans-Activators
  • Veratrum Alkaloids
  • Zinc Finger Protein GLI1
  • cyclopamine