Glucagonomas of transgenic mice express a wide range of general neuroendocrine markers and bioactive peptides.
Pancreatic tumours of transgenic mice carrying a glucagon-promoted simian virus 40 (SV40) T antigen oncogene have been analysed by histological, histochemical, ultrastructural and radioimmunological means. Seven transgenic mice were examined revealing dysplastic and neoplastic lesions in the endocrine pancreas. Four tumours were identified, one of which metastasized to periadrenal spaces and paravertebral lymph nodes. Benign tumours were composed of argyrophilic, endocrine cells reactive to a range of antibodies against neuroendocrine markers (neuron-specific enolase, protein gene product 9.5, chromogranin A, synaptophysin and protein 7B2) and different fragments of the proglucagon molecule (glucagon, glicentin, glucagon-like polypeptides 1 and 2). A few tumour cells expressed pancreatic polypeptide, somatostatin or insulin. Conventional ultrastructural analysis and immunogold labelling revealed typical glucagon-immunoreactive alpha granules which co-stored glicentin and glucagon-like polypeptides 1 and 2. The malignant primary tumour and its metastases were composed mainly of cells which did not show immunoreactivity for neuroendocrine markers or peptides. Atypical, glucagon-immunogold labelled granules were detected at electron microscopy in differentiated tumour cells and C-type retroviral particles in the largest tumour population of degranulated cells. The transgene-encoded oncoprotein SV40 large T-antigen was detected in the nuclei of well-differentiated tumour cells and in alpha cells of some dysplastic islets. All tumour-bearing mice showed high levels of circulating glucagon-like immunoreactivity. Transgenic mice harbouring the glucagon-promoted SV40 T antigen oncogene may provide a model for human glucagonoma.
Department of Histochemistry, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
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G
Rindi
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Efrat
M A
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Ghatei
S R
SR
Bloom
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Solcia
J M
JM
Polak
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D015415:Biomarkers; D005934:Glucagon / Q000032:analysis / Q000235:genetics; D052216:Glucagon-Like Peptide 1; D005935:Glucagonoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010191:Pancreatic Polypeptide / Q000032:analysis; D010446:Peptide Fragments / Q000032:analysis; D052336:Proglucagon; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics; D011863:Radioimmunoassay; D013004:Somatostatin / Q000032:analysis
D000952:Antigens, Polyomavirus Transforming; D015415:Biomarkers; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D013004:Somatostatin; D052336:Proglucagon; D010191:Pancreatic Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon