Development of colonic and pancreatic endocrine tumours in mice expressing a glucagon-SV40 T antigen transgene.
We report the histological, immunohistochemical and ultrastructural changes in mice containing a chimeric glucagon-simian virus 40 T antigen (SV40Tag) gene. Transgene expression was detected in endocrine cells of pancreas, small and large intestine. Hyperplasia of glucagon-containing cells developed in pancreas and large bowel by gestational day 19. In large bowel, hyperplastic cells increased in number postnatally and invasive carcinomas were identified at 4 weeks; several animals had lymph node metastases. In contrast, no pathology was detected in the small bowel in any of the transgenic mice. Colonic tumours expressed SV40Tag, proglucagon-derived peptides and peptide YY (PYY); scattered cells contained cholecystokinin or glycoprotein hormone alpha-subunit. Somatostatin or serotonin was also detected in some tumours. By electron microscopy, the colonic tumours retained features of endocrine differentiation, but secretory granules were smaller than those of non-tumorous intestinal glucagon-producing L cells. In postnatal pancreas, atypical cells containing SV40Tag and glucagon were initially clustered at the periphery of islets; this atypical hyperplasia progressed to neoplasia by 11-12 weeks. Some neoplastic pancreatic cells contained glucagon, PYY or vasoactive intestinal peptide immunopositivity, but most were negative for all peptides; they contained immunoreactivity for tyrosine hydroxylase and by electron microscopy, pancreatic tumour cells had neuronal features. Pancreatic polypeptide was not detected in the non-tumorous islets of transgenic animals. This line of transgenic mice provides a model for the analysis of endocrine tumour progression in the gut and pancreas.
Asa
S L
SL
Department of Pathology, Mount Sinai Hospital, Toronto, Ontario, Canada.
Lee
Y C
YC
Drucker
D J
DJ
D007516:Adenoma, Islet Cell / Q000737:chemistry / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D000367:Age Factors; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005934:Glucagon / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure
D000952:Antigens, Polyomavirus Transforming; D005934:Glucagon