American Journal of Respiratory Critical Care Medicine. 2014 September 4. [Epub ahead of print] [Link]
Schelch K, Hoda MA, Kilkovits T, Munzker K, Ghanim B, Wagner C, Garay T, Laszio V, Setinek U, Dome B, Filipits M, Oirker C, Heffeter P, Selzer E, Tovari J, Torok S, Kenessey I, Holzmann K, Graso-Kraupp B, Marian B, Klepetko W, Berger W, Hegedus B, Grusch M.
Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome and limited therapeutic options. Fibroblast growth factors and their receptors are potential targets for cancer therapy but their significance in mesothelioma has remained largely undefined.
To investigate the anti-mesothelioma potential of fibroblast growth factor receptor 1 inhibition.
Expression of fibroblast growth factors and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate fibroblast growth factor receptor 1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation.
Measurements and Main Results
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 and mitogenic signaling as well as apoptosis induction were also observed in vivo. Importantly, 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 fibroblast growth factor signals, which consequently should be considered as therapeutic targets with a promising chemo- and radio-sensitizing potential.