Molecular and Cellular Biochemistry

, Volume 396, Issue 1–2, pp 257–268 | Cite as

Activated hedgehog pathway is a potential target for pharmacological intervention in biliary tract cancer

  • Tobias Kiesslich
  • Christian Mayr
  • Julia Wachter
  • Doris Bach
  • Julia Fuereder
  • Andrej Wagner
  • Beate Alinger
  • Martin Pichler
  • Pietro Di Fazio
  • Matthias Ocker
  • Frieder Berr
  • Daniel NeureiterEmail author


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.


Biliary tract cancer Hedgehog Oncogenic signalling Pharmacological inhibition Cyclopamine Gant-61 



This study was supported by funds of the Oesterreichische Nationalbank (Anniversary fund, project number: 14842), the research fund of the Paracelsus Medical University Salzburg (Grant No. A-12/02/006-KIE) and the ‘Wissenschaftlicher Verein‘of the Institute of Pathology Salzburg. The authors are grateful to the pharmacy at Salzburger Landeskliniken for providing cisplatin.

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

11010_2014_2161_MOESM1_ESM.pdf (58 kb)
Supplementary material 1 (PDF 57 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Tobias Kiesslich
    • 1
    • 2
  • Christian Mayr
    • 1
  • Julia Wachter
    • 1
    • 3
  • Doris Bach
    • 1
  • Julia Fuereder
    • 1
  • Andrej Wagner
    • 1
  • Beate Alinger
    • 4
  • Martin Pichler
    • 5
  • Pietro Di Fazio
    • 6
  • Matthias Ocker
    • 7
    • 8
  • Frieder Berr
    • 1
  • Daniel Neureiter
    • 4
    Email author
  1. 1.Department of Internal Medicine IParacelsus Medical University/Salzburger Landeskliniken (SALK)SalzburgAustria
  2. 2.Institute of Physiology and PathophysiologyParacelsus Medical UniversitySalzburgAustria
  3. 3.Department of Internal Medicine IILandesklinikum Gänserndorf-MistelbachMistelbachAustria
  4. 4.Institute of PathologyParacelsus Medical University/Salzburger Landeskliniken (SALK)SalzburgAustria
  5. 5.Department of Experimental TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.Department of Visceral, Thoracic and Vascular SurgeryPhilipps-University MarburgMarburgGermany
  7. 7.Institute for Surgical ResearchPhilipps-University MarburgMarburgGermany
  8. 8.Experimental Medicine OncologyBayer Pharma AGBerlinGermany

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