Malignant pleural mesothelioma : novel biomarkers and related pathways

Malignant mesothelioma is an asbestos induced cancer that is difficult to diagnose. Several studies have combined biomarkers to improve mesothelioma diagnosis, but with moderate success, and there is a need for new mesothelioma biomarkers. The tumour is often resistant to treatment and most patients will survive less than a year. An indicator of patient survival is the tumours growth pattern, which in turn is influenced by expressed proteoglycans.

In this thesis work, we aim to improve the possibilities to diagnose malignant mesothelioma by combining biomarkers and by identifying new ones. We also investigate tumour driving mechanisms with focus on one of these suggested biomarkers, the cell-bound proteoglycan syndecan-1.

We were able to construct a diagnostic two-step model based on biomarkers in patient material. By implementing a cut-off level and thereafter focusing on unresolved patients we combined hyaluronan and N-ERC/mesothelin (paper I), which significantly increased the diagnostic accuracy for malignant mesothelioma. To further improve diagnosis, we used mass spectrometry to find new biomarkers. We identified and validated galectin-1, which was excellent in discriminating mesotheliomas from adenocarcinomas (paper II). In the same study, we were also the first to describe aldo-keto reductase 1B10 as a novel prognostic mesothelioma biomarker.

Syndecan-1 has been indicated as a marker for carcinomas. In paper I we describe how higher levels of syndecan-1 indicate the presence of a carcinoma over a mesothelioma. This was verified in paper II when syndecan-1 was identified as downregulated in fluids from mesothelioma patients compared to lung cancer patients. Paper III and paper IV focus on this proteoglycan.

Malignant cell lines transfected with syndecan-1 and various truncated forms of syndecan-1 affected adhesion and migration, which are key features of cancer invasion (paper III). The results showed a domain- and cell type specific effect on the cells’ motility. Regulating syndecan-1 levels and analysing the global gene expression of mesothelioma cells made it evident that this proteoglycan has a strong influence on transforming growth factor β signalling and several growth factor pathways (paper IV). Links to cell migration and proliferation were furthermore identified, along with glycosaminoglycan modifying enzymes. These results can shed light on the complex role of syndecan-1 in invasion and growth of malignant mesenchymal cells.

Taken together, this thesis work describes a complement to conventional mesothelioma diagnosis and identifies novel biomarkers. Furthermore, the potential biomarker syndecan-1 was shown to have an effect on cell motility and proliferation. These results increase our understanding of this aggressive malignancy.

List of scientific papers

I. Filip Mundt, Gustav Nilsonne, Sertaç Arslan, Karola Csürös, Gunnar Hillerdal, Huseyin Yildirim, Muzaffer Metintas, Katalin Dobra and Anders Hjerpe. Pleural effusion biomarkers for diagnosis of malignant mesothelioma. [Manuscript]

II. Filip Mundt, Henrik Johansson, Jenny Forshed, Sertaç Arslan, Muzaffer Metintas, Katalin Dobra, Janne Lehtiö and Anders Hjerpe. Proteome screening identifies galectin-1 as a negative predictor for malignant mesothelioma in pleural effusions. [Manuscript]

III. Fang Zong, Eleni Fthenou, Filip Mundt, Tünde Szatmári, Ilona Kovalszky, László Szilák, David Brodin, George Tzanakakis, Anders Hjerpe and Katalin Dobra. Specific syndecan-1 domains regulate mesenchymal tumor cell adhesion, motility and migration. PLoS ONE. 2011; 6(6): e14816.
https://doi.org/10.1371/journal.pone.0014816

IV. Tünde Szatmári, Filip Mundt, Ghazal Heidari-Hamedani, Fang Zong, Elena Ferolla, Andrey Alexeyenko, Anders Hjerpe and Katalin Dobra. Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells. PLoS ONE. 2012; 7(10): e48091.
https://doi.org/10.1371/journal.pone.0048091