Insertion into the mouse genome of the hybrid oncogene made up of bovine vasopressin gene derived 5′ upstream sequences and the coding sequences of SV40 large T-antigen promoted tumours in anterior pituitary and endocrine pancreas of mice bearing this transgene. In order to investigate the morphology of the steps in the neoplastic process, we used light and electron microscopy to study these organs in 42 animals belonging to the 3rd, 4th and 5th generations, subdivided into 4 age groups from 20 days to 100 days of life. Antibodies to large T-antigen were used to identify sites of expression of the hybrid oncogene, thus monitoring the steps in neoplastic transformation. Large T-antigen immunoreactivity was identified in dysplastic lesions of younger animals and in both dysplastic lesions and tumours of older mice. Insulin (100% of cases) and pancreatic polypeptide (25% of cases) immunoreactivities were revealed in pancreatic lesions but no hormonal immunoreactivity was detected in the pituitary lesions. The ultrastructural study confirmed that the majority cell population of the pancreatic neoplasms was B-type and that the anterior pituitary tumours were poorly granulated. The subcellular localization of large T-antigen immunoreactivity was investigated by the immunogold method and was confined to the heterochromatin of tumour cell nuclei. These findings provide evidence for the dysplasia-neoplasia sequence in the genesis of endocrine tumours of pituitary and pancreas of transgenic mice. The vasopressin-SV40 large T-antigen transgenic mice may therefore be an useful model for the study of endocrine cell oncogenesis,

The authors have used transgenic mice to study the activity of a hybrid oncogene made up of 1.25 kb of 5' upstream sequences, derived from the bovine vasopressin gene, promoting the expression of the large T-antigen coding sequences of the early region of simian virus 40. Rather than promoting tumorigenesis in vasopressinergic cells of the hypothalamus, expression and activity of the hybrid oncogene, and consequent tumor formation, were confined to insulin-producing beta cells of the endocrine pancreas and to cells in the anterior pituitary. These observations suggest that the specificity of vasopressin gene expression normally results from an interaction between several regulatory elements, some of which are absent from the hybrid oncogene. The possible relationship between the endocrine tumor syndrome found in the vasopressin-SV40 transgenic mice and familial human multiple endocrine neoplasia is discussed.