title: Hedgehog pathway as a potential treatment target in human cholangiocarcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Campus Virchow Clinic, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Riedlinger
authors.forename: Marcus
authors.initials: M
authors.lastname: Bahra
authors.forename: Sabine
authors.initials: S
authors.lastname: Boas-Knoop
authors.forename: Steffen
authors.initials: S
authors.lastname: Lippert
authors.forename: Maren
authors.initials: M
authors.lastname: Bradtmöller
authors.forename: Katrin
authors.initials: K
authors.lastname: Guse
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.forename: Roberta
authors.initials: R
authors.lastname: Bova
authors.forename: Igor M
authors.initials: IM
authors.lastname: Sauer
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.forename: Carsten
authors.initials: C
authors.lastname: Kamphues
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D001653:Bile Ducts, Intrahepatic; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D005260:Female; D015870:Gene Expression; D005839:Gentamicins / Q000008:administration & dosage / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000235:genetics; D000072079:Patched Receptors; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: C583051:BMS-833923; D001549:Benzamides; D005839:Gentamicins; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D011799:Quinazolines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine
keywords: Cholangiocarcinoma; Gemcitabine; Hedgehog proteins; Molecular targeted therapy; Sonic Hedgehog inhibitor