Cell lines from human mesotheliomas have been shown to express the platelet-derived growth factor (PDGF)-A gene product, while normal human mesothelial cells do not. A T-antigen immortalized human mesothelial cell overexpressing PDGF-A chain was shown to be tumorigenic. Analysis of the receptor-ligand interactions in this cell line, human mesothelioma cell lines and normal and T-antigen expressing, non-tumorigenic human mesothelial cells aims to identify mechanisms of carcinogenesis. Platelet-derived growth factor receptor (PDGFR)-alpha but not PDGFR-beta expression is down regulated in mesothelioma as compared to normal mesothelial cells. A model human mesothelial cell in which PDGFR-alpha is expressed has been identified. This system will be utilized to investigate the transcriptional control of this receptor and its relevance to pathogenesis of the disease. In an attempt to identify inactivated tumor suppressor pathways, mesothelioma cell lines in which the p53 gene had been shown to be wild type or mutant were studied for expression of the MDM2 gene product. Results of these analyses indicated that overexpression of MDM2 was not a frequent occurrence in mesothelioma cell lines. However, cell lines with p53 mutations contained the lowest levels of MDM2. It has been shown previously that mesothelioma cells contain normal levels of the Rb protein. Recent experiments show that five of five mesothelioma cell lines have homozygous deletions of p16, a candidate tumor suppressor gene localized to chromosome 9p21-22, a site whose loss is commonly associated with mesothelioma. Deletion of the function of this gene would block the G1 arrest induced by Rb, inactivating this important check on cell division and error-prone DNA synthesis.
