Mesothelioma is an asbestos associated tumor arising from mesothelial cells that line the body cavities. Although the etiology of asbestos induced mesothelioma has been well described, very little is known about the molecular alterations that cause these tumors. Our lack of knowledge regarding the molecular events that cause mesothelioma has hampered efforts to identify alternative fibers that can be used as safe asbestos substitutes and has contributed to a diagnostic dilemma in the identification of these tumors. The long range goal of this research is to understand how asbestos fibers transform mesothelial cells. To achieve this goal, the general approach is to identify molecular alterations that occur in transformed mesothelial cells and elucidate the mechanism by which asbestos fibers caused these alterations. The proposed studies are designed to determine the role of the Wilms' tumor (WT-1) suppressor gene in normal and malignant mesothelial cells.
Specific Aims are to 1) Determine the expression pattern of the WT 1 gene in normal and transformed rat mesothelial cells. The expression of the 4 splice variants of WT-1 in normal and transformed mesothelial cells will be examined by PCR to identify differences in gene processing between normal and transformed cells. Using in situ hybridization, WT-1 expression patterns will be correlated with histological subtypes (epithelial, fibrous, mixed) of mesotheliomas to determine if gene expression is regulated by cell differentiation. 2) Identify alterations in the WT-1 gene in transformed rat mesothelial cells. Mutations at the WT-1 gene locus will be identified in cell lines isolated from transformed rat mesothelial cells (spontaneous and asbestos-induced) using direct sequencing of PCR amplified CDNA. To gain information regarding the function of WT-1 in transformed cells, rat mesothelioma cell lines will be transfected with wild type WT-1 to determine the ability of this gene to suppress the transformed phenotype. 3) Establish the similarity or difference in WT-1 alterations between rat and human mesothelioma. Data obtained from the rat cell lines will be expanded to primary rat tumors induced by asbestos and human mesotheliomas to determine if WT-1 is a putative target gene for asbestos. The usefulness of this gene as a biomarker to discriminate between mesothelioma and parenchymal lung tumors will be determined by examining the pattern of expression/alterations in the WT-1 gene in other types of human lung cancer. Information resulting from this research will yield new diagnostic strategies for the identification of mesothelioma and yield mechanistic insights on the role of the WT-1 suppressor gene as a putative gene target for asbestos in mesothelioma development. In addition, these studies will contribute to our knowledge regarding the WT-1 locus by elucidating the function of this gene in an extra-renal neoplasm.
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