The underlying molecular pathology of cancer of the exocrine pancreas in humans and animal models of the disease is poorly understood, particularly with regard to the role of tumor suppressor gene (TSG) alterations in its development and malignant progression. The proposed studies will characterize the frequency and nature of molecular alterations in the p53, Rb-1, and DCC TSGs in human sporadic and familial cases of pancreatic cancer and their relationship to the clinicopathologic presentation of the disease and patient survival status. The TSGs will be examined by immunochemical and molecular approaches in a panel of tumor-derived cell lines and fresh frozen and archival tumor material. The role of these TSGs in pancreatic tumorigenesis, in vivo invasiveness, metastatic spread, and tumor morphological and secretory differentiation will be examined in TSG replacement studies in tumor cell lines in which the endogenous TSG(s) is (are) mutated or altered in their expression. In order to understand the role of TSG alterations in the development of human pancreatic cancer, in which early and intermediate lesions are rare or absent, the N-nitrosobis (2-oxopropyl)amine (-BOP)-induced ductal pancreatic carcinoma model in syrian hamsters will be utilized as a paradigm for studying the temporal sequence of molecular alterations during human pancreatic tumorigenesis based upon its morphological, biological, and molecular biological correlates with the human cancer. Collectively, these studies will provide a greater understanding of the molecular pathology of pancreatic cancer and the role and potential prognostic significance of several TSGs in the multi-step process of pancreatic tumorigenesis in humans and a highly relevant animal model of the disease.
