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

Karin Schelch, Christina Wagner, Sonja Hager, Christine Pirker, Katharina Siess, Elisabeth Lang, Ruby Lin, Michaela B. Kirschner, Thomas Mohr, Luka Brcic, Brigitte Marian, Klaus Holzmann, Bettina Grasl-Kraupp, Georg Krupitza, Viktoria Laszlo, Thomas Klikovits, B. Döme, B. Hegedűs, Tamas Garay, Glen ReidNico van Zandwijk, Walter Klepetko, Walter Berger, Michael Grusch, Mir Alireza Hoda

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 TGFß 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.

Original languageEnglish
Pages (from-to)534-545
Number of pages12
JournalCarcinogenesis
Volume39
Issue number4
DOIs
Publication statusPublished - Apr 5 2018

ASJC Scopus subject areas

  • Cancer Research

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    Schelch, K., Wagner, C., Hager, S., Pirker, C., Siess, K., Lang, E., Lin, R., Kirschner, M. B., Mohr, T., Brcic, L., Marian, B., Holzmann, K., Grasl-Kraupp, B., Krupitza, G., Laszlo, V., Klikovits, T., Döme, B., Hegedűs, B., Garay, T., ... Hoda, M. A. (2018). FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal. Carcinogenesis, 39(4), 534-545. https://doi.org/10.1093/carcin/bgy018