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

Content Provider	Springer Nature Link
Author	Kiesslich, Tobias Mayr, Christian Wachter, Julia Bach, Doris Fuereder, Julia Wagner, Andrej Alinger, Beate Pichler, Martin Di Fazio, Pietro Ocker, Matthias Berr, Frieder Neureiter, Daniel
Copyright Year	2014
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.
Starting Page	257
Ending Page	268
Page Count	12
File Format	PDF
ISSN	03008177
Journal	Molecular and Cellular Biochemistry
Volume Number	396
Issue Number	1-2
e-ISSN	15734919
Language	English
Publisher	Springer US
Publisher Date	2014-07-27
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Biliary tract cancer Hedgehog Oncogenic signalling Pharmacological inhibition Cyclopamine Gant-61 Biochemistry Medical Biochemistry Oncology Cardiology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Clinical Biochemistry Molecular Biology

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