Oxidized derivatives of dipropylnitrosamine administered to the Syrian golden hamster induce adenocarcinoma of the pancreatic ducts bearing a strong morphologic and biological resemblance to its counterpart in humans. Since carcinomas of the exocrine pancreas in particular those arising in ducts represent the most prevalent form of pancreatic cancer in humans, this model has been the focus of considerable research. Important findings obtained from its study that meant further consideration include the biological significance of the limited activation of these from its study that merit further consideration include the biological significance of the limited activation of these carcinogens by the pancreas as compared to liver, and the high resistance of the pancreatic ducts of the rat to chemical carcinogenesis. In addition, pancreatic duct cells which represent only 4% of the cell population of the pancreas have not until recently been successfully maintained in culture for extended periods so that detailed analysis of the genetic and functional events involved in their neoplastic transformation is now possible. In view of the foregoing, we propose to investigate the following testable hypotheses: that intrapancreatic metabolism of carcinogen by acinar and duct cells plays a role in pancreatic carcinogenesis, that the susceptibility of pancreatic ducts in the hamster and their resistance in the rat are attributable to differences in DNA damage and repair, that a series of definable key intracellular events and adaptive cellular changes occur during the malignant transformation of duct cells, that the cooperativity of various immortalizing and transforming oncogenes depend on their relative levels of expression and perhaps sequence of activation, and that important hitherto unrecognized genes remain to be identified in pancreatic ductal carcinogenesis. The major specific aims of this project are: 1) To identify and characterize the 15 and 17KD proteins secreted by normal hamster pancreatic duct cell monolayers and determine their tissue distribution and expression during ontogenesis of the pancreas and liver; 2) To ascertain if duct cells alone or cocultured with acinar or liver cells can undergo mutation following exposure to direct or indirect acting carcinogens; 3) To compare DNA damage by direct or indirect acting carcinogens and its repair in cultured hamster pancreatic duct cells with those of a rat; 4) To identify the sequence of genetic cytologic and functional phenotypic alterations that occur in hamster duct cells following exposure to methylnitrosourea (MNU), or (2-hydroxyptopyl) nitrosourea (HPNU); 5) To characterize the cooperativity of various immortalizing and transforming oncogenes in malignant transformation by transfecting them at different levels of expression into normal hamster pancreatic duct cells; and 6) To identify the genes that are expressed and/or not expressed in the neoplastic transformation of hamster duct cells using subtraction library screening.
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