Due to the many genetic changes that can occur during oncogenesis and due to the fact that normal human cells are difficult to grow and are highly resistant to transformation, in vitro experimental systems that address multiple genetic events in carcinogenesis have been difficult to develop. We have developed such a system using the human teratocarcinoma cell line PA-1 from which independent variants that are nontumorigenic (preneoplastic) have been isolated, requiring either 1 or 2 oncogenes to become tumorigenic as well as numerous transformed tumorigenic cell lines. Since PA-1 cells can be induced to differentiate, we are able to study carcinogenesis and differentiation in the same model system. We will analyze cellular mechanisms of transformation in ras resistant and ras transformable preneoplastic PA-1 cells and the regulatory role of tumor suppressors in this process. We will determine the role of suppressor genes in the carcinogenic process in PA-1 cell tumors by with regard to their control of signal transduction through growth factor receptors. We will determine how the processes of transformation and differentiation are jointly affected in the biology of PA-1 teratocarcinoma cells by studying the effect of oncogenes and suppressors on cellular processes that directly (or indirectly) affect differentiation and differentiation modulated gene expression. We will determine how the state of transformation in these cells affects retinoid responsive genes such as homeobox genes and the transcription factor AP-2. In this fashion we hope to impact a major question in cancer biology: How do ras oncogenes alter the growth and differentiation of epithelial cancers? Since 50% of colon and lung cancers contain activated ras oncogenes, a mechanistic understanding of these processes will have a great impact on a large fraction of neoplasia in adults.
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