It is the goal of this project to determine how the interaction of mesothelial cells with the fiber carcinogen, asbestos, leads to the development of mesothelioma. We have previously shown that mesotheliomas over express PDGF-A. We have further shown that T antigen-immortalized human mesothelial cells become tumorigenic after transfection with an expression vector for PDGF-A. A mechanistic understanding of this tumorigenic conversion became problematic when it was reported that the PDGF-alpha receptor was not expressed in mesothelioma cell lines. We have investigated the expression of the two receptors for PDGF. Results show that the PDGFR-alpha is expressed in mesotheliomas but at a level much below that of normal mesothelial cells. Furthermore, in experiments with normal mesothelial cells which express the PDGF-alpha receptor at high levels, we showed that treatment with PDGF-A, as expected, decreased receptor expression. Initial experiments using suramin to block cell surface ligand-receptor interactions in mesothelioma suggest that this is part of the explanation for the down regulation of this receptor. The finding that residual receptor is expressed suggests that this amount of receptor, when fully activated by autocrine ligand, may contribute significantly to oncogenic pathways of signal transduction. In additional experiments, we are treating mesothelial cells, in vitro, with asbestos. We have repeated the finding that this treatment generates mesothelial cell populations with extended life span. We are characterizing these populations with respect to genes which have recently been implicated in senescence and immortalization and are lost in mesothelioma.
