Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors.

Fourteen hormone-producing gastrointestinal tract tumors were tested for their content of somatostatin (SRIH) receptors, using receptor autoradiography and in vitro binding assay with tumor homogenates. All four gastrinomas tested had high levels of SRIH receptors, as did two of five insulinomas and four of five vasoactive intestinal peptide-producing tumors. Receptor visualization was obtained with two different radioligands, either a SRIH-28 analog, [125I]-[Leu8,D-Trp22,Tyr25]SRIH-28, or a SRIH octapeptide, the [125I]Tyr3 derivative of SMS 201-995 [H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr(ol)], [125I]204-090. In both cases receptors were localized over the tumor cell area only. Biochemical and pharmacological analyses of one insulinoma and two vipomas revealed saturable, high affinity binding sites with pharmacological specificity for SRIH. However, differences in receptor affinity of selected SRIH analogs, in particular SRIH-28 and SRIH octapeptides, were found between the insulinomas and the two other tumor types, vipoma and gastrinoma. The presence of SRIH receptors on various hormone-producing gastrointestinal tumors suggests that at least part of the beneficial effects of chronic therapy with SRIH analogs may be mediated through such membrane-bound receptors located on the tumor itself. SRIH receptor measurement may be of prognostic value in assessment of the therapeutic efficacy of SRIH analogs. They may also be of diagnostic value, if used as in vivo markers for the localization of small hormone-producing gastrointestinal tumors or their metastases.

The isolation and sequence analysis of vasoactive intestinal peptide from a ganglioneuroblastoma.

A ganglioneuroblastoma was excised at surgery from a 1-yr-old girl with severe watery diarrhea. The tumor, weighing 1 g, was extracted in trifluoracetic acid and contained 8.3 nmol immunoreactive vasoactive intestinal peptide. The peptide was isolated by affinity chromatography and high pressure liquid chromatography and was found to be identical to porcine vasoactive intestinal peptide by amino acid analysis and microsequence analysis.

The morphology and neuroendocrine profile of pancreatic epithelial VIPomas and extrapancreatic, VIP-producing, neurogenic tumors.

The histology, histochemistry, and ultrastructure of 43 VIP-producing tumors (34 from the pancreas, one jejunal, six retroperitoneal and two mediastinic), 37 of which were associated with the WDHA syndrome, have been investigated on paraffin sections of primary or metastatic tumor tissue. The pancreatic and jejunal tumors showed all structural and secretory patterns of epithelial endocrine tumors, including expression of cytokeratin, neuroendocrine markers like neuron-specific enolase, chromogranins and synaptophysin, peptides like VIP, PHM, GRH, PP, insulin, neurotensin, glucagon, somatostatin and enkephalin, secretory granules, small clear vesicles, peculiar osmiophilic bodies, and occasional formation of tubules or microacini with specialized luminal surfaces. All the remaining tumors were neurogenic, showing either neurons and nerve fibers together with Schwann cells (ganglioneuromas and ganglioneuroblastomas) or endocrine cells (pheochromocytomas) reacting with VIP, PHM, NPY, enkephalin, somatostatin, neuron-specific enolase, synaptophysin, and MAP2 (but not cytokeratin, PP, or GRH) antibodies. A possible origin of pancreatic VIPomas from transformed pancreatic PP cells or ductular stem cells partially committed to differentiation along the PP cell line is suggested.

Carcinoid tumor of the pancreas causing the diarrheogenic syndrome: report of a case combined with multiple endocrine neoplasia, type I.

A case of carcinoid tumor of the pancreas with the watery diarrhea, hypokalemia, and hypochlorhydria syndrome in association with hyperparathyroidism and the amenorrhea-galactorrhea syndrome is presented. Resection of the three grossly enlarged, hyperplastic parathyroid glands restored eucalcemia in this patient. A subsequent excision of the 370 gm pancreatic carcinoid tumor resulted in a cure of the watery diarrhea and a return of the gastric acid secretion to normal. Immunocytochemical studies of the pancreatic tumor demonstrated a positive stain only for serotonin, and negative results for vasoactive intestinal polypeptide, pancreatic polypeptide, glucagon, insulin, cholecystokinin, gastrin, and calcitonin were obtained. These studies suggest that in this patient, serotonin was a causative agent of the watery diarrhea syndrome.

Pancreatic endocrine tumours associated with WDHA syndrome. An immunohistochemical and electron microscopic study.

Nine pancreatic endocrine tumours of patients with watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome were examined by immunohistochemistry and electron microscopy. All cases revealed neoplastic proliferation of VIP (vasoactive intestinal peptide)-immunoreactive (IR) cells. Immunoreactivity to a novel peptide hormone PHM-27, which is processed from a common big precursor peptide of VIP (prepro VIP/PHM-27), was identified in VIP-IR cells of 8 tumours. VIP-PHM-IR cells had secretory granules measuring about 130 to 220 nm in diameter. Radioimmunoassay of tumour tissue extracts showed high VIP and PHM contents in proportional amounts in most cases. According to the results of immunostaining, the 8 tumours fell into two large groups; 5 with PP (pancreatic polypeptide)-IR cells and 3 with CT (calcitonin)-IR cells. The former group demonstrated VIP cells and PP cells intermingled in various proportions, including one tumour in which coexistence of PP-IR and VIP-IR in the same cells was demonstrated. Cell heterogeneity of the tumours and possible relationships of VIP, PP and CT cells were discussed.

Immunochemical characterization of a novel secretory protein (defined by monoclonal antibody HISL-19) of peptide hormone producing cells which is distinct from chromogranin A, B, and C.

In this study we have investigated the biochemical properties as well as the subcellular localization of a 67 kD (35/32 kD dimer) polypeptide detected by a monoclonal antibody (HISL-19), which was generated after immunization of BALB/c mice with human islet cell preparations. This protein is expressed by neuronal and peptide hormone producing cells and shares many biochemical and molecular key features with the chromogranin proteins. As demonstrated by one-dimensional and two-dimensional gel electrophoresis, immunoblotting, monoclonal antibody HISL-19 immunoaffinity chromatography, and immunoelectron microscopy, it is a water-soluble, acidic protein stored within secretory granules of peptide hormone-producing cells, and it is released in detectable amounts into the serum of patients bearing neuroendocrine carcinomas. Differences of the HISL-19 protein and chromogranins A, B, and C are indicated by their different tissue distribution, the discrepancy of their apparent molecular weights in sodium dodecyl sulfate gels and isoelectric points, and by the lack of cross-reactivity of their specific antibodies. The protein detected by monoclonal antibody HISL-19 represents therefore a novel component of the soluble compartments of neurosecretory granules, which is distinct from chromogranin A, B, and C.