NEOPLASTIC TRANSFORMATION OF PROPAGABLE CULTURED RAT PANCREATIC DUCT EPITHELIAL-CELLS BY AZASERINE AND STREPTOZOTOCIN

The role of duct cells in the histogenesis of pancreatic carcinoma was studied using a propagable cultured pancreatic duct epithelial cell l ine derived from a Fischer-344 rat. Tumorigenic transformation was ind uced by treatment with two experimental pancreatic carcinogens, azaser ine and streptozotocin, or spontaneously using a 'selective' culture c ondition. Tumors arising from spontaneously transformed cells were ana plastic carcinomas, while those from streptozotocin-transformed celts were well or moderately differentiated ductal adenocarcinomas. Azaseri ne-treated cells produced moderately to poorly differentiated adenocar cinomas. Ultrastructural evidence of acinar or endocrine differentiati on was absent. The biochemical phenotypes of representative tumor cell lines established from these tumors were studied. As compared to the parental cell line which expressed high activity of carbonic anhydrase (CA) and negligible activity of gamma-glutamyl transpeptidase (GGT), the tumor cell lines displayed variably increased levels of GGT, and a diminution or loss of CA activity. The tumor cell lines also showed h eterogeneity in proto-oncogene and growth factor/receptor expression. The transforming growth factor-alpha mRNA expression was increased in all tumor cell lines, especially in those induced by azaserine. In con trast, mRNA expression of epidermal growth factor receptor was markedl y down-regulated in all tumor cell lines. AH chemically induced tumor cell lines showed marked overexpression of the c-myc and c-Ki-ras mRNA s, whereas the spontaneously transformed tumor cell line showed only a significant overexpression of the c-Ki-ras. Point mutation of this pr oto-oncogene at codons 12, 13 or 61 was absent. The results show that azaserine and streptozotocin are potent carcinogens in vitro for cultu red rat pancreatic duct epithelial cells, and the phenotype of the tum ors is modulated by the method or agent used for their transformation.