Understanding the progression of biological events associated with the development of malignancies is an important goal of cancer research. Identification of gene products which are expressed during the development of carcinomas can provide a method for following the evolution of the malignant prototype, possibly in relation to associated, underlying changes in gene expression. Monoclonal antibodies can identify individual antigens from complex immunogens, can demonstrate the intracellular location of antigens, and also identify antigen positive cells in a heterogeneous cell population, and are therefore well suited to probe for phenotypic changes. Hepatic carinoma and its precursors will be induced in rats with chemical carcinogens (a modified Toronto/Solt-Farber protocol) and monoclonal antibodies which bind to hepatic carcinoma cells will be developed. Initially, mice will be immunized with hepatoma tumor or cell line homogenates and monoclonal antibodies which bind to the immunogen, but not to normal rat liver homogenate, will be identified. Preparation of these antibodies is technically feasible using either this or alternative strategies. Antigen expression will be evaluated by immunohistologic demonstration of antibody binding to normal liver and to carcinogen induced hepatic lesions including early foci, early and persistent nodules, and invasive or metastatic carcinoma. In later experiments early or persistent nodules will be used as immunogens to permit detection of antigens which are transiently expressed in the development of this carcinoma. These antibodies will also be assayed for binding to other rat and human malignancies, particularly hepatic cancers, to regenerating liver, to fetal liver and to normal adult rat organs. Antigens of particular interest will be those associated with invasive or metastic carcinoma, with precursor stages, or with a variety of malignancies. To identify genes which code for any such antigens, an expression vector which contains a rat hepatic carcinoma cDNA library will be constructed and antibodies which bind these antigens will screen the gene products. The relevant genes may then be cloned and used in future studies. These molecular biology studies will be done only if antigens of sufficient potential are identified, and then will be performed in concert with those members of Lieberman's group who are investigating gene expression in this carcinoma model.
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