Hedgehog Pathway in HNSCC: A Target in Future Therapies?

Abstract

Objective: Demonstrate the expression of components of the Hedgehog signaling pathway (Hh) in HNSCC. A subsequent over-stimulation of this pathway is described in several types of malignancies and is associated with poor prognosis. Hh inhibition with antagonists like Cyclopamin (Cyc) may reveal a potential therapeutic relevance. Method: iParaffin-embedded sections of 10 HNSCC were incubated with Alexa 568-labeled antibodies specific for Hh proteins. Further, we tested the effects of Cyc on the growth of KB cells and on HNSCC cells ex vivo in FLAVINO-bioassays alone and in combination with chemotherapeutic agents. Immunofluorescent colonies of epithelial cells were counted. Results: Epithelial cells in HNSCC expressed components of the Hh-pathway (PTCH-1, PTCH-2, SMO, GLI, andSHH) preferentially at the invading tumor margins. The intensity and distribution of the staining was heterogeneous but significant. Peritumoral stroma cells stained partly positive, too. Cyc alone suppressed mitosis and proliferation of KB cells and suppressed the formation of cytokeratin-positive (CK+) colonies of HNSCC ex vivo in a concentration dependent manner. Further, Cyc enhanced the inhibitory effects of Cisplatin (Cis) and Docetaxel (DTX) on colony formation of CK+ cells in the KB cell line and in HNSCC ex vivo. Conclusion: Our results underline a potential relevance of Hh in HNSCC. Additional targeting of Hh components may support established therapy regimens in HNSCC-treatment in the future and, therefore, represents a promising aim for drug discovery.