title: Activated hedgehog pathway is a potential target for pharmacological intervention in biliary tract cancer.
abstract: Hedgehog (Hh) signalling contributes to carcinogenesis and represents a valid druggable target in human cancers, possibly also in biliary tract cancer (BTC). We analysed the expression of Hh components in BTC using eight heterogeneously differentiated cell lines, xenograft tumours and a human tissue microarray. The dose-, time- and cell line-dependent effects of two Hh inhibitors (cyclopamine and Gant-61) were analysed in vitro for survival, apoptosis, cell cycle distribution and possible synergism with conventional chemotherapeutic agents. In human BTC samples, the sonic Hh ligand and the Gli1 transcription factor showed increased expression in tumours compared to normal adjacent tissue and were significantly associated with high tumour grade and positive lymph node status. In BTC cell lines, we could confirm the Hh component expression at varying extent within the employed cell lines in vitro and in vivo indicating non-canonical signalling. Both Hh inhibitors showed dose-dependent cytotoxicity above 5 µM with a stronger effect for Gant-61 inducing apoptosis whereas cyclopamine rather inhibited proliferation. Cytotoxicity was associated with low cytokeratin expression and higher mesenchymal marker expression such as vimentin. Additionally, drug combinations of Gant-61 with conventional chemotherapy (cisplatin) exerted synergistic effects. In conclusion, Hh pathway is significantly activated in human BTC tissue compared to normal adjacent tissue. The current data demonstrate for the first time an effective anticancer activity of especially Gant-61 in BTC and suggest second generation Hh pathway inhibitors as a potential novel treatment strategy in BTC.
authors: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
authors: Tobias
authors: T
authors: Kiesslich
authors: Christian
authors: C
authors: Mayr
authors: Julia
authors: J
authors: Wachter
authors: Doris
authors: D
authors: Bach
authors: Julia
authors: J
authors: Fuereder
authors: Andrej
authors: A
authors: Wagner
authors: Beate
authors: B
authors: Alinger
authors: Martin
authors: M
authors: Pichler
authors: Pietro
authors: P
authors: Di Fazio
authors: Matthias
authors: M
authors: Ocker
authors: Frieder
authors: F
authors: Berr
authors: Daniel
authors: D
authors: Neureiter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy / Q000379:methods; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; C551027:GANT 61; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D002945:Cisplatin; C000541:cyclopamine