TARGETED ONCOGENESIS OF HORMONE-NEGATIVE PANCREATIC-ISLET PROGENITOR CELLS

Transgenic mice containing an upstream glucokinase (beta GK) promoter- simian virus 40 T antigen (Tag) fusion gene develop neuroendocrine tum ors primarily in the pancreas, gut, and pituitary. Pancreatic tumors f rom a line with delayed tumorigenesis were of two different types: ins ulinomas and noninsulinomas. The noninsulinomas are often periductal i n location, express none of the four major islet peptide hormones, Glu t-2, Pdx1, tyrosine hydroxylase, Pax4, Pax6, or Nkx6.1, but do express glucokinase, Sur1, Isl1, Hnf3 beta, Hnf6, Beta2/NeuroD, and Nkx2.2. C ells from two different noninsulinoma tumors, when adapted to culture, began to express either insulin, glucagon, or somatostatin. Given the partial gene expression repertoire of the noninsulinoma tumors, their apparent periductal origin, and the ability of these cells to partial ly cytodifferentiate in culture, we suggest that these tumors are deri ved from islet progenitor cells. Thus, beta GK-Tag transgenic mice pro vide a new model system for studying the events that occur during both islet cell neogenesis and normal embryonic development.