Experimental therapeutics against malignant mesothelioma : Investigations in vitro

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Sammanfattning: Malignant mesothelioma is a tumour of the mesothelium, a specialized tissue found in the pleura, pericardium, peritoneum, and tunica vaginalis testis. The tumour has strong etiological links to asbestos, with a latency period ranging up to several decades between asbestos exposure and tumour diagnosis. Treatment is mostly ineffective and the median survival is around 12 months. The tumour exhibits an interesting and peculiar heterogeneity; tumour cells may assume either an epithelioid or a sarcomatoid phenotype. Presence of the sarcomatoid phenotype is a predictor for therapy resistance and a worse prognosis. In this work, we have investigated the anticancer effects of selenite, a small ion formed by the oxidation of selenium. We show that selenite can induce cell death and apoptosis in malignant mesothelioma cells. The specific signalling pathways have been delineated. Furthermore, we have shown that selenite sensitizes mesothelioma cells to NK-cell mediated recognition and killing. Specifically, we have shown that selenite exerts its anticancer effects in cells of both phenotypes through the induction of oxidative stress. Apoptosis is induced through the mitochondrial pathway. Differences in the activation pattern of Bcl-family proteins could be observed between cells of the two phenotypes. Interestingly, p53 protein was enriched in the nuclei of selenite-treated cells, but in a form bereft of its DNA-binding ability. We hypothesise that this is explained by redox inactivation due to the prooxidant effects of selenite. Perturbation of the apoptosis signalling network by inhibition of key mediators had very little effect, suggesting that the network is robust through functional redundancy. A systematic testing of selenite in a panel of six cell lines of varying differentiation alone and together with conventional drugs showed that the cells were resistant in general, but all cell lines were sensitive to at least one of the tested drugs. Synergistic effects between selenite and other drugs were limited. Phenotype was a poor predictor of response. These results highlight the need for improved personalisation of mesothelioma treatment. In the last sub-project, we have showed that selenite sensitizes mesothelioma cells to NK-cell mediated killing. A search for alterations in NK-cell receptor ligand expression revealed that the inhibitory ligand HLA-E was down-regulated on tumour cells in response to selenite. Further analyses showed that the mRNA expression for HLA-E remained constant during selenite treatment, while the intracellular and surface protein levels decreased, and that increased recognition by NK cells was dependent on HLA-E downregulation rather that on modulation of other NK cell ligands. These results indicate that selenite is a potential new drug against malignant mesothelioma. Further trials are warranted to determine the safety and efficacy of selenite in a clinical setting.

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