The proposed research with pancreatic acinar carcinomas, established as transplantable tumors in F344 and Wistar/Lewis rats, is based on the postulate that neoplasia results from disordered cell differentiation. The mechanisms underlying cell differentiation and gene expression are to be explored by systematic comparative investigations of morphogenetic, cytologic, biochemical and functional differences between normal and neoplastic exocrine pancreatic acinar epithelium. The cellular heterogeneity in F344 rat transplantable pancreatic acinar carcinoma provides an appropriate model system for characterizing the domains of gene expression within each cytodifferentiated state. The major areas to be investigated include: 1) an analysis of the total and secretory proteins synthesized by the secretory granule-enriched (GE) and secretory granule-deficient (GD) neoplastic subpopulations; 2) determination of whether the newly identified protein p24 in the secretory granule protein is transformation-related; 3) definition of the nature of the markedly reduced Mr 80,000 glycoprotein in the secretory granule membrane; 4) an attempt to define and compare the patterns of gene expression in normal pancreas and transplantable pancreatic acinar carcinomas and the GE and GD subpopulations, by in vitro translation; 5) an analysis of the sulfated glycoproteins and glycosaminoglycans in tumor subpopulations to define their relevance to secretory protein concentration in GD neoplastic cells; 6) development of in vitro culture systems to maintain and modulate the neoplastic cells with different phenotypes. The techniques involved in these studies would be, tumor transplantation cell culture, light and electron microscopic autoradiography, two-dimensional gel electrophoresis, subcellular fractionation and in vitro translation. We anticipate that proposed studies with further our knowledge of the biological behavior of pancreatic acinar carcinoma and that study of the abnormal might reveal cellular polypeptides or other pertinent information involved in regulating cell proliferation and cytodifferentiation.
