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

Molecular and cellular biochemistry (2014-07-30)
Tobias Kiesslich, Christian Mayr, Julia Wachter, Doris Bach, Julia Fuereder, Andrej Wagner, Beate Alinger, Martin Pichler, Pietro Di Fazio, Matthias Ocker, Frieder Berr, Daniel Neureiter
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resazurin sodium salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Resazurin sodium salt, certified by the Biological Stain Commission