Malignant Mesothelioma: Virus, Biomarkers and Genes- a Translational Approach
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Malignant mesothelioma is an asbestos-related, lethal treatment resistant tumour with increasing incidence worldwide. In four translational studies we have studied the pathogenesis of mesothelioma with regard to the SV40 virus, we have examined biomarkers in serum and tumour, related to risk and prognosis and carried out genome-wide profiling for a deeper understanding of mesothelioma biology. Simian Virus 40 (SV40), a Rhesus monkey virus, was a contaminant of the polio vaccine between 1956-1963, during which time millions were vaccinated, also in Norway. It is an oncogenic virus in some animals, immortalizes and transforms human cells, and its DNA has been detected in human tumours, among them mesothelioma. The role of SV40 in human carcinogenesis is very controversial. In the first study we tested pre-diagnostic (1-30 years) sera from 49 mesothelioma cases and 147 matched controls for antibodies against the viral capsid protein VP1, the large T antigen of SV40, the closely related human polyomaviruses BK and JC, and for SV40 DNA. Our conclusion was that no SV40 DNA was detected and that no significant association was seen between SV40 antibody response in pre-diagnostic sera and risk of mesothelioma. Soluble Mesothelin-Related Protein (SMRP) in serum is a novel marker for diagnosis and progression of mesothelioma and a potential screening marker. Likewise, mesothelin protein expression in tumors is regarded as a sensitive marker for diagnosis and disease progression, and is a candidate prognostic marker. In the second study, pre-diagnostic (1-30 years) serum levels of SMRP, CA125 and CYFRA 21-1 from 47 mesothelioma cases and 141 matched controls were analysed. Mesothelin expression in tumors was assessed with immunohistochemistry. Our conclusion was that there was no significant association between biomarker levels and mesothelioma risk, but mesothelin expression in <50% of tumor cells was a significant negative prognostic marker in all cases of malignant mesothelioma in univariate analysis (median survival = 6 months vs. 12 months, hazard ratio (HR) = 2.49, 95%CI 1.17—5.27). Mesothelioma of the epithelial type arising in the peritoneum had a significantly longer survival than epithelial type in pleura. This was also reflected in mesothelin expression. Pleural mesothelioma develops in the parietal pleura, subsequently invading the visceral pleura. The parietal pleura, is thus the optimal control tissue for gene profiling. In the third paper we describe genome-wide profiling of human biopsies from pleural mesothelioma, and normal parietal and visceral pleura analyzed by Affymetrix Human Genome U133 Plus 2.0 Chip with 38 500 genes. Distinct expression profiles of the three tissues were detected. The cell cycle, M-phase, DNA replication and repair, anti-apoptosis and proteasome genes, pathways and gene ontology entities were highly overexpressed in mesothelioma, reflecting tumor growth and intrinsic resistance. Furthermore several experimental targets were overexpressed as well. Genes of the ”salvage pathway” that recycle nucleobases, such as TYMS, the target of the drug pemetrexed, were overexpressed. NME1 and NME2 overexpression may contribute to the locally invasive, non-metastatic phenotype of mesothelioma. Circadian rhythm genes were expressed in favour of uncontrolled tumour growth. Conversely, genes involved in cell communication, adhesion and leukocyte endothelial migration were down-regulated, reflecting a tumour phenotype that isolates itself from the immune and inflammatory systems. GSTM1 down-regulation in tumour could play a general role in mesothelioma susceptibility. The normal parietal pleura profile showed downregulation of signal transduction and adhesion compared to the visceral pleura. This could indicate a genotypical basis of increased susceptibility of the parietal pleura to develop mesothelioma. In the fourth paper, based on the microarray analysis of tumour versus parietal pleura, we discovered a close relation between gene profile and resistance to topoisomerases, antitubulines, antifolates, platinum compounds and radiation therapy. Several known gene and pathway targets of chemo- and radiotherapy were overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for DNA double-strand break repair by homologous recombination, may be a key pathway in mesothelioma chemo-and radio-resistance.. CHEK1, RAD21 and RAN are proposed as co-targets for mesothelioma treatment. The novel proangiogenic AGGF1 was highly over-expressed in all tumours and may be a target for antiangiogenic treatment. Over-expression of NQO1 may render mesothelioma sensitive to the effect of the novel compound beta-Lapachone . Targeted suppression of some of these key genes and pathways combined with chemotherapy or radiation could theoretically improve outcome in mesothelioma and possibly other aggressive malignancies. Other resistant cancers have recently been found to overexpress several genes related to DNA repair and replication. This feature, along with other findings, suggests that the mesothelioma genome-wide profile may serve as a general model of tumour resistance.
UtgiverNorges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for kreftforskning og molekylær medisin
SerieDoktoravhandlinger ved NTNU, 1503-8181; 2008:275
Dissertations at the Faculty of Medicine, 0805-7680; 370