Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schelch, K; Hoda, MA; Klikovits, T; Münzker, J; Ghanim, B; Wagner, C; Garay, T; Laszlo, V; Setinek, U; Dome, B; Filipits, M; Pirker, C; Heffeter, P; Selzer, E; Tovari, J; Torok, S; Kenessey, I; Holzmann, K; Grasl-Kraupp, B; Marian, B; Klepetko, W; Berger, W; Hegedus, B; Grusch, M.
Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.
Am J Respir Crit Care Med. 2014; 190(7):763-772
Doi: 10.1164/rccm.201404-0658OC
Web of Science
PubMed
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FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Münzker Julia
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- Abstract:
- Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined. To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition. Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation. FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin. Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Antineoplastic Agents - pharmacology
- Apoptosis - drug effects
- Apoptosis - genetics
- Cell Line, Tumor -
- Cell Proliferation - drug effects
- Cell Proliferation - genetics
- Cell Survival - drug effects
- Cell Survival - genetics
- Cisplatin - pharmacology
- Combined Modality Therapy - methods
- Disease Models, Animal -
- Humans -
- Lung Neoplasms - drug therapy
- Lung Neoplasms - genetics
- Lung Neoplasms - radiotherapy
- Mesothelioma - drug therapy
- Mesothelioma - genetics
- Mesothelioma - radiotherapy
- Mice -
- Protein Kinase Inhibitors - pharmacology
- Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1 - drug effects
- Receptor, Fibroblast Growth Factor, Type 1 - genetics
- Signal Transduction - drug effects
- Signal Transduction - genetics
- Find related publications in this database (Keywords)
- asbestos-related malignancy
- fibroblast growth factors
- molecular targeted therapy
- combined modality therapy