Expression of hedgehog signalling pathway in anaplastic thyroid cancer
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ORIGINAL ARTICLE
Expression of hedgehog signalling pathway in anaplastic thyroid cancer Ulrike Hinterseher • Annette Wunderlich • Silvia Roth • Annette Ramaswamy • Detlef K. Bartsch • Stefan Hauptmann Brandon H. Greene • Volker Fendrich • Sebastian Hoffmann
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Received: 20 April 2013 / Accepted: 4 July 2013 Ó Springer Science+Business Media New York 2013
Abstract The purpose of this work is to study the activation of the hedgehog signalling pathway is associated with tumour progression in various types of cancer, hence the development of specific antagonists raises hope for new therapeutic strategies. Therefore, the expression of hedgehog pathway components in anaplastic thyroid cancer (ATC) and effects of the hedgehog inhibitor Cyclopamine on ATC cells were investigated in this study. Expression of the ligand Sonic Hedgehog (SHh), the transmembrane protein Smoothened (Smo), the receptor Patched (Ptc) and the target gene Gli-1 was evaluated in two ATC cell lines (Hth 74, C643) by RT-PCR and in tumour specimens by immunohistochemistry. The corresponding gene products were examined by western blotting analysis. After treatment with different concentrations of Cyclopamine the time-dependent course of cell viability in ATC cell lines was evaluated by MTT assay. SHh, Smo, Ptc and Gli were clearly expressed on mRNA and protein levels in both cell lines and in tumour samples (41 %SHh, 65 %Smo, U. Hinterseher A. Wunderlich S. Roth D. K. Bartsch V. Fendrich S. Hoffmann (&) Department of Visceral, Thoracic- and Vascular Surgery, University Hospital Marburg, Baldingerstrasse, 35043 Marburg, Germany e-mail: [email protected] A. Ramaswamy Department of Pathology, University Hospital Marburg, Marburg, Germany S. Hauptmann Department of Pathology, University Hospital Halle-Saale, Marburg, Germany B. H. Greene Department of Biometrics, Philipps University, Marburg, Germany
65 %Ptc and 65 %Gli). Treatment with Cyclopamine showed a time- and dose-dependent inhibition of cell numbers with IC50 values between 1 and 4 lM in both cell lines, comparable to other types of cancer. In conclusion, we believe that the hedgehog pathway is expressed in anaplastic thyroid carcinoma specimens and proliferation of ATC cell lines can be influenced by the Hh inhibitor Cyclopamine. Aberrant activation of this pathway might be involved in the aggressive biology of anaplastic cancer and further evaluation regarding a possible clinical impact of pathway inhibition is warranted. Keywords Hedgehog signalling pathway Cyclopamine Anaplastic thyroid cancer MTA
Introduction Carcinomas of the thyroid gland are the most common malignant diseases of the endocrine system, displaying a rising incidence in recent years. Although only 1–2 % of thyroid cancers (TC) are anaplastic [1] they contribute to up to 50 % of the TC associated mortality with a median survival of 3–5 months [2]. The reason for this is the failure of standard therapeutic procedures in anaplastic thyroid cancer (ATC), as well as its resistance to conventional chemot
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