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 line derived from a Fischer-344 rat. Tumorigenic transformation was induced by treatment with two experimental pancreatic carcinogens, azaserine and streptozotocin, or spontaneously using a ‘selective’ culture condition. Tumors arising from spontaneously transformed cells were anaplastic carcinomas, while those from streptozotocin-transformed cells were well or moderately differentiated ductal adenocarcinomas. Azaserine-treated cells produced moderately to poorly differentiated adenocarcinomas. Ultrastructural evidence of acinar or endocrine differentiation 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 γ-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 heterogeneity in proto-oncogene and growth factor/receptor expression. The transforming growth factor-α mRNA expression was increased in all tumor cell lines, especially in those induced by azaserine. In contrast, mRNA expression of epidermal growth factor receptor was markedly down-regulated in all tumor cell lines. All chemically induced tumor cell lines showed marked overexpression of the c-myc and c-Ki-ras mRNAs, whereas the spontaneously transformed tumor cell line showed only a significant overexpression of the c-Ki-ras. Point mutation of this proto-oncogene at codons 12, 13 or 61 was absent. The results show that azaserine and streptozotocin are potent carcinogens in vitro for cultured rat pancreatic duct epithelial cells, and the phenotype of the tumors is modulated by the method or agent used for their transformation.