Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours

Abstract

Chromogranins and/or secretogranins constitute a family of water-soluble acidic glycoproteins that are present in almost all endocrine, neuroendocrine and neuronal tissue. Antibodies against chromogranins have been widely used for immunohistochemical staining of endocrine tissue and tumours of neuroendocrine origin. Furthermore, measurements of circulating chromogranin A have been used as a reliable marker for neuroendocrine tumour growth. In this study, we describe the development of specific antibodies against chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin. The antibodies were used for immunohistochemical staining of normal and neoplastic neuroendocrine tissue and development of reliable radioimmunoassays for chromogranin A, chromogranin B, chromogranin C and pancreastatin. In 44 patients with carcinoid tumours, 17 patients with sporadic endocrine pancreatic tumours and 11 patients with endocrine pancreatic tumours and the multiple endocrine neoplasia 1 syndrome, plasma measurements revealed elevated chromogranin A levels in 99%, elevated chromogranin B in 88%, elevated chromogranin C in 6% and elevated pancreastatin in 46% of the patients. Urinary measurements revealed elevated levels in 39%, 15%, 14% and 33% of the patients respectively. Gel permeation chromatography of plasma and urine showed that circulating chromogranin A, and immunoreactive fragments of chromogranin A, had a higher molecular weight distribution than the chromogranin A fragments excreted to the urine. Furthermore, it was noted that most of the patients excreting chromogranin A fragments to the urine had previously been treated with streptozotocin, a cytotoxic agent known to induce renal tubular dysfunction. The antibodies raised proved useful for immunohistochemical staining and visualised endocrine cells in pancreatic islets, adrenal medulla and the small intestine as well as in endocrine pancreatic tumours, pheochromocytoma and midgut carcinoid tumours. In conclusion, the antibodies raised were useful for both immunohistochemical staining of normal tissue and endocrine tumours as well as development of specific radioimmunoassays for plasma measurements of the different chromogranins. Furthermore, we show that plasma measurements of chromogranin A and B were superior to measurements of chromogranin C and pancreastatin and plasma measurements of the different chromogranins were more reliable as markers for tumour growth than the corresponding urine measurements.

A new human chromogranin A (CgA) immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145-245)

“…Although it could be speculated that the detection of a more restricted fragment could correlate to total CgA measurement, it has been shown that the assessment of plasma pancreastatin, produced by cleavage at the 243 and 294 dibasic sites, was less discriminative and of less clinical interest than that of total CgA (Stridsberg et al, 1995). Our results show that the hCgA C-terminal end is particularly affected by degradation, but that proteolysis decreases when moving upstream in the sequence.…”

“…Levels of total circulating hCgA are significantly elevated in phaeochromocytomas, carcinoid and pancreatic endocrine tumours (O'Connor and Deftos, 1986). These data have been confirmed and extended to other neoplasia: neuroblastoma and gastrointestinal tumours (Eriksson et al, 1990;Hsiao et al, 1990;Stridsberg et al, 1995). Other authors have also described how the occurrence of plasma hCgA in prostatic carcinoma may be the sign of an unfavourable evolution (Cussenot et al, 1996;Deftos et al, 1996).…”

Tachykinins in endocrine tumors and the carcinoid syndrome

“…The antibodies and the synthesized peptide were used to develop a specific RIA. For preparation of the tracer, the peptide was labeled with 125 I (Amersham International plc, Amersham) using the chloramine-T method as previously described (24). The assay was devised as follows: standards and unknown samples were incubated with a tracer (30 000 c.p.m./tube) and primary antibodies, at a final dilution of 1/45 000, for 3 days at C4 8C.…”

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Ileal carcinoids are composed of enterochromaffin cells that secrete serotonin and tachykinins, which may give rise to hormonal symptoms. Other tumour markers are chromogranin A and vesicular monoamine transporter 1 (Stridsberg et al 1995, Jakobsen et al 2001. The aetiology of ileal carcinoids is unknown.…”