Anne von Mässenhausen1,2,3, Mario Deng4,5, Hannah Billig1,2,3, Angela Queisser1,2,3, Wenzel Vogel4,5, Glen Kristiansen2,3, Andreas Schröck3,6, Friedrich Bootz3,6, Friederike Göke1,2,3, Alina Franzen1,2,3, Lynn Heasley7, Jutta Kirfel2,3, Johannes Brägelmann1,3,8, Sven Perner9,10. 1. Section of Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany. 2. Institute of Pathology, University Hospital of Bonn, Bonn, Germany. 3. Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany. 4. Pathology of the University Hospital of Luebeck, Luebeck, Germany. 5. Department of Pathology, Leibniz Research Center Borstel, Borstel, Germany. 6. Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital of Bonn, Bonn, Germany. 7. Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 8. Department of Hematology/Oncology, University Hospital of Bonn, Bonn, Germany. 9. Pathology of the University Hospital of Luebeck, Luebeck, Germany. Sven.Perner@uksh.de. 10. Department of Pathology, Leibniz Research Center Borstel, Borstel, Germany. Sven.Perner@uksh.de.
Abstract
BACKGROUND: Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). AIMS: The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC. METHODS: FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment. RESULTS: Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398. CONCLUSIONS: Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.
BACKGROUND: Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). AIMS: The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC. METHODS:FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment. RESULTS: Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398. CONCLUSIONS: Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.
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