Expression and processing of progastrin were examined in fetal, neonatal, and adult pancreatic tissue from five mammalian species (cat, dog, man, pig, and rat). A library of sensitive, sequence-specific immunoassays for progastrin and its products was used to monitor extractions and chromatography before and after cleavage with processing-like enzymes. The results showed that progastrin and its products are expressed in the pancreas of all species in total concentrations varying from 0.3 to 58.9 pmol/g of tissue (medians). The degree of processing was age-and species-dependent. In comparison with adult pancreatic tissue the fetal or neonatal pancreas processed a higher fraction to bioactive, C-terminally amidated gastrin. Nevertheless, the pancreatic processing was always less complete than that of the adult antral mucosa. The moderate level of expression and the attenuated processing in the adult pancreas contribute to explain previous failures to detect gastrin in normal pancreatic tissue. Our results indicate that gastrin-producing tumors in the pancreas are not ectopic, but arise from cells that normally express the gastrin gene.Gastrin stimulates the secretion of gastric acid and growth of the fundic mucosa (1). Accordingly, gastrin-producing tumors (gastrinomas) induce hypersecretion of acid with ensuing duodenal ulcer disease and fundic mucosal hypertrophy, i.e., the Zollinger-Ellison syndrome. By far most gastrinomas originate in the pancreas, although gastrin normally is synthesized in the antroduodenal mucosa. Gastrinomas are nevertheless a frequent type of endocrine tumor in the human pancreas (2, 3) and have been found also in dogs (4, 5).The pancreatic origin of gastrinomas has been an enigma. Insulinomas, glucagonomas, somatostatinomas, pancreaticpolypeptide tumors (PPomas), and vasoactive intestinal polypeptide tumors (VIPomas) all have cellular counterparts that express the corresponding hormone in the normal pancreas. In contrast, attempts to detect gastrin in the normal pancreas have so far either failed (6-10) or resulted in the misidentification of somatostatin cells as gastrin cells (11)(12)(13). The only reproducible exception has been the apparently transient gastrin synthesis in the fetal and neonatal rat pancreas (14)(15)(16)(17)(18).Deduction of the sequence of mammalian preprogastrins (19)(20)(21) has paved the way for development of radioimmunoassays for progastrin and its processing intermediates (22-25). Such radioimmunoassays have proved useful for studies ofgastrin biosynthesis in tissues known to express the gastrin gene (24-29). The observation of expression but attenuated processing of progastrin in the normal pituitary (29) suggested that progastrin might be expressed also in the normal pancreas, and hence explain the gastrinoma enigma (30). This hypothesis has now been examined. NOMENCLATUREMammalian preprogastrins comprise 101-104 amino acid residues (19-21). They have an N-terminal signal sequence, a spacer sequence, the sequence containing the major bioactive form...