Abstract
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.
Highlights
Chromogranins/secretogranins or granins (Cgs) represent a family of secretory proteins that occur in large dense-core vesicles of endocrine, neuroendocrine and neuronal cells [1,2]
We examined the relevance of combining the measurement of WE-14, chromogranin A (CgA) and EM66, in comparison to CgA alone, for the potential improvement of the diagnostic sensitivity for this tumor
Previous studies have established that WE-14 is a distinct neuropeptide produced by cell-specific proteolysis of CgA in various neuronal and neuroendocrine tissues [40]
Summary
Chromogranins/secretogranins or granins (Cgs) represent a family of secretory proteins that occur in large dense-core vesicles of endocrine, neuroendocrine and neuronal cells [1,2]. The proteolytic cleavage of SgII generates secretoneurin (SN), EM66 and manserin Their ubiquitous distribution in endocrine and neuroendocrine tissues and their co-secretion with resident peptide hormones and biogenic amines, make granins and their derived peptides useful markers of secretion from neuroendocrine cells and neoplasms [6]. Measurement of CgA levels in plasma can be used to diagnose or monitor the progression of neuroendocrine tumors [8]. It has been reported that the CgA-derived peptide vasostatin I may help to distinguish between metastatic deposits originating from ileum or lung carcinoid primary tumors [12], and that plasma levels of GAWK and CCB, two CgBderived peptides, are elevated in patients with pancreatic islet-cell tumors [13,14] or with bronchial tumors [15]. High concentrations of SgII have been found in ganglioneuromas and neuroblastomas [16], while high plasma SN concentrations are associated with several neuroendocrine tumors [17] and with progression of neuroendocrine prostatic carcinomas [18]
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