During the past five years we have been developing transgenic models of oncogenesis and studying their characteristics. In these experiments the transforming oncogenes from simian virus 40 (SV40), activated ras, and c-myc have been expressed in liver or pancreas to create several heritable and predictable tumor phenotypes. In these models at least one additional event, the activation of another oncogenic element or the loss of a tumor suppressor factor, appears to be necessary for final transformation to a complete malignant phenotype. Since the basic pattern of the premalignant condition and eventual tumorigenesis is clearly defined in these unique transgenic lines, other genes can now be introduced into mice and expressed in transformed liver or pancreas to determine their influence on the course of tumor formation and progression. Several classes of genes believed to be intricately involved in tumor development (e.g. growth factors, proteases, and antioncogenes) are ideal candidates to study for their effect on tumor phenotypes resulting from oncogenes. Therefore, new lines of mice will be generated that express these genes, and they will be characterized and then crossed to lines of mice that show an oncogene-induced phenotype. The effect of expression of each gene on tumor growth, invasion, and metastasis will then be assessed. We have three specific aims: 1. We will determine if growth factors (including transforming factor alpha, cholecystokinin, and angiogenin) influence the development and progression of tumors induced by transgenic oncogenes. 2. We will determine if proteases (including collagenase, stromelysin/transin, and urokinase) enhance the invasive or metastatic capability of tumors induced by transgenic oncogenes. 3. We will determine if expression of """"""""tumor suppressor"""""""" genes, (including retinoblastoma and gap junction) interferes with the progression of tumors induced by transgenic oncogenes.
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