chromogranin-a-derived-peptide--we-14 and Neuroendocrine-Tumors

Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Biomarkers; Chromaffin Cells; Chromogranin A; Female; Gene Expression Regulation, Neoplastic; Healthy Volunteers; Humans; Male; Middle Aged; Mutation; Neoplasm Proteins; Neuroendocrine Tumors; Peptides; Pheochromocytoma; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity; Young Adult

Antisera were generated to the synthetic peptides SREWEDS and KELTAE which correspond to residues 315-321 and 332-337 of human chromogranin A (CgA) respectively. KELTAE represents the C-terminal hexapeptide of WE-14, and SREWEDS (residue 316 human CgA Lys/Arg substitution) represents the C-terminal heptapeptide of the Intervening Peptide, located between pancreastatin and WE-14. The antisera were employed to study the occurrence of WE-14 and CgA-derived peptides in human and bovine gastro-entero-pancreatic (GEP) tissues and in a range of human GEP neuroendocrine tumours. Immunocytochemical analyses of normal human and bovine tissues demonstrated that each antiserum immunostained endocrine cells throughout the GEP tract, Variable intensities of immunostaining were detected in neoplastic tissues. Quantitatively, the highest levels of SREWEDS and KELTAE immunoreactivity were detected in pancreatic extracts, with lower levels in gastrointestinal tissues. Elevated levels of each immunoreactant were detected in neoplastic tissues. Chromatographic analysis resolved several SREWEDS-related peptides and a major KELTAE-related peptide that co-eluted with synthetic human WE-14. The present study has demonstrated that CgA is processed to generate distinct peptide products in normal and neoplastic tissues of the GEP system. A single molecular species co-eluting with synthetic human WE-14 was predominant and consistently detected in all the tissues studied.

Topics: Aged; Animals; Cattle; Chromatography, Gel; Chromogranin A; Chromogranins; Digestive System; Female; Humans; Immune Sera; Immunohistochemistry; Male; Middle Aged; Neoplasm Proteins; Neuroendocrine Tumors; Pancreas; Peptide Fragments