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Carcinogenesis. 2018 Apr 5;39(4):534-545. doi: 10.1093/carcin/bgy018.

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal.

Author information

Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Asbestos Diseases Research Institute (ADRI), Sydney, NSW, Australia.
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Institute of Pathology, Medical University of Graz, Graz, Austria.
Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna.
Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary.
MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, University of Duisburg-Essen, Essen, Germany.
School of Medicine, University of Sydney, NSW, Australia.


Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.

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