Endocrine
tumors of the pancreas may produce characteristic syndromes attributable to the increased secretion of one or more
hormones. These
tumors provide valuable opportunities for the analysis of
hormone biosynthesis and secretion in the neoplastic human endocrine cell. The authors studied a pancreatic endocrine
tumor obtained from a patient with classical
glucagonoma syndrome. Characterization of plasma and
tumor glucagon-like immunoreactivity (GLI) by high-performance liquid chromatography and radioimmunoassay for GLI showed different chromatographic profiles, with
glucagon the major molecular form in the
tumor, and
glicentin and
oxyntomodulin predominating in plasma. Although immunocytochemical staining of the
tumor showed only focal weak positivity for
glucagon,
tumor extracts contained large amounts of immunoreactive GLI
peptide. Northern blot analysis of
tumor RNA demonstrated that abundant
glucagon mRNA transcripts were present, just slightly larger in size than those detected in normal pancreas and intestine. Electron microscopic analysis of the
tumor cellular ultrastructure revealed only occasional small electron dense secretory granules. A large number of complex lysosome-like structures of variable size and electron density were detected throughout the cytoplasm and ringing the nucleus of most cells, a feature atypical of endocrine
tumors of the pancreas. Primary cultures of dispersed
tumor cells were established and, in contrast to previous results, were obtained using normal or neoplastic islet cell models, GLI secretion was found to be stimulated eightfold by incubation with 5 mM dibutyryl cyclic
adenosine monophosphate.
Phorbol myristate acetate, the
calcium ionophore A23187, and
sodium butyrate had no effect on GLI secretion in vitro. These observations indicate that neoplastic human A cells may have abnormalities at different points in the biosynthesis and secretion of
glucagon.