P34. Exploring cell plasticity in malignant pleural mesothelioma

Background: Malignant Pleural Mesothelioma (MPM) is a relatively rare, highly aggressive tumor which originates from pleural mesothelial cells. It has three distinct histological subtypes: the epithelioid, the sarcomatoid (which has a more fibroblast-like morphology than the epithelioid) and the biphasic subtype, the latter being a mixed type of the others. MPM is highly resistant to current chemo- and radiotherapy, resulting in a poor prognosis. Epithelial mesenchymal transition (EMT) is a process best known for its role in development, but it is also known to be involved in the progression of cancer and in chemoresistance. During this process typical epithelial characteristics like cell-polarity and junctions between the cells are lost, and the cells gain migratory and invasive abilities. Understanding of the role of EMT in MPM is currently very limited. Aim of this study was to characterize the influence of growth factors, especially fibroblast growth factor 2 (FGF2), on MPM cell lines regarding EMT-like changes.

Methods: Changes in the gene and miRNA expression were determined by qPCR and array hybridisation. To characterize the influence of growth factors and/or inhibitors, various treatments (and treatment combinations) were applied to MPM cells in migration and proliferation assays. For analysis of involved downstream signalling pathways immunoblotting was used.

Results: Treatment with FGF2 or EGF induced a transition to a more fibroblastoid/sarcomatoid morphology in several biphasic MPM cell lines, transmitted by the MAP kinase pathway. Other cytokines like TGF-β, HGF or PDGF did not induce these changes. Additionally also the migration of the FGF2 treated cells increased. Several epithelial markers were down-regulated and mesenchymal markers were up-regulated in the treated cell lines, suggesting not only a switch to a more sarcomatoid morphology but also an underlying EMT in those cells. In addition to the expression-changes of typical EMT-markers some novel FGF2/EGF regulated genes were identified. FGF2 treatment also affected microRNA expression, possibly accounting for some of the observed alterations in the expression of protein-coding genes.

Conclusions: These cell lines from biphasic MPM may represent interesting models to study the link between EMT, histological subtype and tumor progression in MPM.

Keywords: Pleura mesothelioma; cell structure