Chromogranin A (CgA) is a 439 amino acid protein secreted by neuroendocrine cells. Proteolytic processing of CgA results in the production of different bioactive peptides. These peptides have been associated with inflammatory bowel disease, diabetes, and cancer. One of the chromogranin A-derived peptides is ∼52 amino acid long Pancreastatin (PST: human (h)CgA250-301, murine (m)CgA263-314). PST is a glycogenolytic peptide that inhibits glucose-induced insulin secretion from pancreatic islet β-cells. In addition to this metabolic role, evidence is emerging that PST also has inflammatory properties. This review will discuss the immunomodulatory properties of PST and its possible mechanisms of action and regulation. Moreover, this review will discuss the potential translation to humans and how PST may be an interesting therapeutic target for treating inflammatory diseases.

Chromogranins belong to the family of secretory chromogranin and secretogranin proteins. They are found in secretory vesicles throughout the neuroendocrine system. Chromogranin A (CgA) is the main component. CgA acts as a prohormone submitted to processes of degradation through which active peptides are generated. CgA has auto, para and endocrine functions. It is widely used as an immunohistochemical marker. Despite the lack of international standardization, and the lack of an accurate definition of the diagnostic cut-off levels, some CgA assays are reliable. Numerous studies have suggested that CgA determination may be of interest for the diagnosis and the follow-up of various endocrine tumors. Plasma levels of this general marker are proportional to tumor mass. The localization of the primitive tumor, the presence of associated hormonal secretions and possible renal failure and/or hypergastrinemia must be taken into consideration for proper interpretation of CgA levels. New clinical indications are emerging for the evaluation of stress in intensive care units and the assessment of cardiovascular risk. New assays estimating the concentration of active peptides are under development.

The diagnostic impact of chromogranin A (CgA) measurement has been studied in various neuroendocrine tumours (NET) such as pheochromocytomas, gastrinomas and neuroblastomas. Clinically nonfunctioning pituitary adenomas (NFPA) are generally diagnosed on tumoural symptoms or hypopituitarism and, except for gonadotrophins and their free subunits which may be increased in the case of gonadotrophinomas, markers of endocrine secretory activity are lacking not only for diagnostic purpose but also in the postoperative follow-up of these patients. As the presence of CgA has been demonstrated by immunohistochemistry in pituitary adenomas, we performed this study to further assess the sensitivity of CgA measurement in sporadic pituitary adenomas using a new, specific, sandwich immunoassay.

We first completed a basal normative data set obtained using this assay by studying four healthy men (49 +/- 13 years old), five healthy premenopausal women (35.8 +/- 7.5 years old) and five healthy postmenopausal women (49.1 +/- 4.6 years old) basally and after TRH administration. Twenty-seven patients [12 men (64.2 +/- 11.8 years), even premenopausal women (38.4 +/- 5.7 years) and eight postmenopausal women (67.7 +/- 10.3 years)] with NFPA, 15 acromegalic patients [nine men (45 +/- 13.3 years), six women (52 +/- 14.9 years)] and 19 patients with a prolactin-secreting adenoma [four men (41.2 +/- 18 years) and 15 women (31.2 +/- 7.5 years), with a macroadenoma (n = 11) or a microadenoma (n = 8)] had basal and TRH-stimulated measurement of CgA. A gonadotrophin-releasing hormone (GnRH)-stimulation test was also performed in two, four and four patients, respectively. All patients had sporadic pituitary adenomas.

Serum CgA was measured using a solid-phase two-site immunoradiometric assay based on monoclonal antibodies that bind to two distinct contiguous epitopes within the 145-245 region of CgA.

Mean basal CgA concentration in 14 normal subjects was 80.2 ng/ml (SD: 31.7; range 19-124). A cut-off value for normal range was thus set at 125 ng/ml. TRH injection did not change significantly the CgA levels, peak values remaining less than 124 ng/ml. Three out of 27 subjects with NFPA (11%) had elevated basal CgA levels (576, 143, 241 ng/ml, respectively). Serum levels of CgA were not influenced by TRH in any of the NFPA subjects (including those three with increased basal levels). One out of 15 acromegalic patients (6.6%) and one out of 19 hyperprolactinemic patients (5.2%) had elevated serum basal CgA which did not significantly increase after TRH administration. In the remaining patients TRH-tests did not modify CgA levels. GnRH administration did not modify CgA levels.

CgA serum levels measurement, assessed with a novel assay, does not provide a helpful marker for the clinical management of functioning and NFPA.

The expression of various chromogranin A (CgA) peptide fragments was examined with region-specific antisera in benign and malignant pituitary tumors. Analysis of the proconvertases responsible for proteolytic processing of CgA, prohormone convertase 1/3 (PC1/3), and PC2 was also performed. Adenomas were studied using tissue microarrays, and a larger tissue section of a subset of the prolactin (PRL) adenomas was used to compare to the tissue microarray analysis. Carcinomas were analyzed using larger tissue sections. There were differences in CgA proteolytic products detected between the functional (PRL, adrenocorticotropic hormone [ACTH], and growth hormone tumors and the nonfunctional (gonadotroph and null cell) tumors, with the former group expressing lower levels of many peptides. These differences were most notable in the PRL adenomas and carcinomas in which the region-specific antisera against vasostatin I and vasostatin II detected these fragments in the lowest percentage of tumors and/or had the weakest immunoreactivity. The CgA peptide fragment detected by CgA 176-195 (chromacin) antiserum was expressed by the highest percentage of most functional and nonfunctional benign and malignant pituitary tumors. ACTH carcinomas (n = 3) were more strongly immunoreactive compared to the ACTH adenomas. These results show that there is differential expression of CgA peptide fragments and PC1/3 among different types of pituitary tumors and that ACTH pituitary carcinomas have higher levels of immunoreactive CgA peptide fragments compared to ACTH adenomas. This study also shows the utility of tissue microarrays in the analysis of a large group of tumors with regionspecific antisera.

Chromogranin A (CgA), pancreastatin (PST), intervening-peptide (IP) and WE-14 antisera were employed to investigate the proteolysis of CgA in 50 pituitary adenomas. All non-functioning (NF) pituitary tumours (n = 28) exhibited CgA immunoreactivity. PST, IP and WE-14 immunostaining was observed in 85%, 89% and 67%, respectively. CgA, PST and IP immunostaining were comparable in the majority of NF tumours, while less intense WE-14 immunoreactivity was detected in a subpopulation of NF tumour cells. Approximately half of the functioning pituitary tumours expressed CgA immunoreactivity. Six of nine ACTH-secreting tumours displayed CgA and IP immunostaining; four of these tumours displayed PST immunoreactivity. WE-14 immunoreactivity was detected in one corticotroph tumour. Three of six growth hormone (GH) secreting tumours displayed CgA immunostaining, two exhibited PST and IP, and one exhibited WE-14 immunoreactivity. Clusters of WE-14 immunopositive cells were detected in one GH tumour. One of seven prolactinomas exhibited weak CgA immunostaining, while weak IP and WE-14 immunostaining was detected in an additional tumour. No PST immunostaining was detected in prolactinomas. Therefore CgA is a valuable marker of NF pituitary tumours, however it is a more sporadic marker of functioning adenomas. In general, the cellular pattern and intensities of CgA, PST and IP immunoreactivity were comparable in the majority of pituitary adenomas. In contrast, WE-14 immunostaining was observed in a subpopulation of tumour cells. The pathophysiological significance of the proteolysis of CgA to generate bioactive peptides in both NF and functioning pituitary adenomas remains to be established.

Chromogranin A (CgA) belongs to a family of secretory proteins that are present in densecore vesicles of neuroendocrine cells. Owing to its widespread distribution in neuroendocrine tissues, it can be used as an excellent immunohistochemical marker of neoplasms of neuroendocrine origin. It can also serve as serum marker of neuroendocrine activity because it is co-released with the peptide hormone content of the secretory granules. The serum concentration of CgA is elevated in patients with various neuroendocrine tumours. Elevated levels are strongly correlated with tumour volume. Although its sensitivity and specificity cannot compete with that of the specific hormonal secretion products of most of these tumours, it can nevertheless have useful clinical applications. Neuroendocrine tumours for which no peptide marker is available usually retain the capacity to secrete CgA. CgA can thus be used as serum marker for these so-called 'non-functioning' endocrine tumours. Moreover, in patients with carcinoids and phaeochromocytomas, CgA is a more stable and thus more easily manageable marker than plasma levels of respectively serotonin and catecholamines and their urinary metabolites. Its role as an important general neuroendocrine marker may be extended in the future by the development of immunoscintigraphy of membrane-bound CgA, allowing in vivo visualization of neuroendocrine neoplasms.

Neuroendocrine differentiation in carcinoma of the prostate is characterized by the expression of neuroendocrine cell products such as chromogranin A (CgA). We studied serum levels and tissue staining for CgA in prostate cancer to assess their clinical value.

In 82 patients with prostate cancer, serum specimens were obtained at diagnosis and studied by both CgA and prostate-specific antigen (PSA) immunoassays. In 43 additional patients with prostate cancer, paraffin-embedded tissue from core biopsies or transurethral resections and serum samples were studied, respectively, by immunohistology and immunoassay for CgA.

In serum samples from the 82 patients in whom CgA and PSA levels were measured, 26 of 82 (32%) had an elevated CgA (greater than 200 ng/mL), and 36 of 82 (44%) had an elevated PSA (greater than 4.0 ng/mL). Of the patients with Stage D2 cancer, 11 of 18 (61%) had an elevated CgA and 6 of 18 (33%) had an elevated PSA. Four of 5 patients with local recurrence had an elevated CgA, but only 1 patient had an elevated PSA. Of the 43 patients in whom serum and tissue CgA studies were performed, 12 (28%) had elevated serum CgA, and 15 of the 43 (35%) had CgA staining in their prostate tissue. Of the 14 of these patients with D2 disease (distant metastases), 9 (64%) had elevated serum levels of CgA and 6 (43%) had positive staining in their prostate tissue. Of the 9 patients with Stage D2 disease and elevated serum CgA, 6 had a normal serum PSA.

Our studies complement those of others and indicate that CgA has potential as a clinically useful serum and tumor marker for prostate cancer. Serum CgA measurements can identify some patients with advanced disease who do not have elevated serum PSA. However, further studies in larger groups of patients are needed to define the clinical value of CgA as a marker for prostate cancer.

Posttranslational processing of peptide-precursors is nowadays believed to play an important role in the functioning of neurons and endocrine cells. Both proenkephalins and chromogranins/secretogranins are considered as precursor molecules in these tissues, resulting in posttranslationally formed degradation products with potential biological activities. Among the proteins and peptides of neuronal and endocrine secretory granules, the enkephalins and enkephalin-containing peptides have been most extensively studied. The characterization of the post-translationally formed degradation products of the proenkephalins have enabled the understanding of their processing pathway. Chromogranins/secretogranins represent a group of acidic glycoproteins, contained within hormone storage granules. The biochemistry, biogenesis and molecular properties of these proteins have already been studied for 25 years. The chromogranins/secretogranins have a widespread distribution throughout the neuroendocrine system, the adrenal medullary chromaffin granules being the major source of these storage components. Recent data provide evidence for a precursor role for all members of the chromogranins/secretogranins family although also several other functions have been proposed. In this review, some of the methods applied to study proteolytic processing are described. In addition, the posttranslational processing of chromogranins/secretogranins and proenkephalins, especially the biochemical aspects, will be discussed and compared. Recent exciting developments on the generation and identification of potential physiologically active fragments will be covered.

Endocrine-paracrine cells of the prostate (also known as APUD or neuroendocrine cells) constitute, in addition to the basal and exocrine secretory cells, a third population of highly specialized epithelial cells in the prostate gland. These endocrine-paracrine cells contain, and most likely secrete, serotonin and calcitonin, as well as variety of other peptides. Little is known of the functional role of these cells, but they probably subserve a paracrine or local regulatory role. They may also regulate via endocrine, lumencrine, or neurocrine mechanisms. These endocrine-paracrine cells probably play a significant role during prostatic growth and differentiation as well as regulating the secretory process of the mature gland. Neuroendocrine differentiation in prostatic carcinoma occurs in the form of the relatively rare small cell carcinoma and carcinoid or carcinoid-like tumor, but most commonly as focal neuroendocrine differentiation in a conventional prostatic adenocarcinoma that is a very frequent, if not ubiquitous phenomenon, and reflects tumor cell heterogeneity mimicking the normal differentiation process. The world's literature on neuroendocrine differentiation in prostatic carcinoma is reviewed. Neuroendocrine differentiation in all types of prostatic carcinoma appears to correlate with a poor prognosis. This correlation is probably multifactorial and may relate to a positive correlation with grade, a direct resistance to hormonal manipulation, and/or autocrine/paracrine growth factor activity due to the secretion of neuroendocrine products. Neuron-specific enolase and chromogranin, as well as other neuroendocrine products, may be useful as serum markers in patients with prostatic carcinoma with neuroendocrine differentiation. New therapeutic strategies need to be developed to treat these tumors. This includes the use of specialized protocols that have been effective against neuroendocrine carcinomas arising in other organ systems.

Endocrine-paracrine (APUD, neuroendocrine) cells are located in the prostatic ductal and acinar epithelium. These cells are of the open and closed type and have dendritic processes. There is a wide range of secretory granule morphology presumably indicating a variety of different cell "types." Secretory immunoreactive peptides include serotonin, calcitonin (and related peptides), somatostatin, bombesin-like, thyroid-stimulating hormone-like (beta chain), and alpha-glycoprotein chain-like. These cells may function by endocrine, paracrine, neurocrine, and lumencrine mechanisms and play an important regulatory role both during growth and differentiation of the prostate as well as in the secretory process of the mature gland. Neuroendocrine differentiation in prostatic carcinoma is a frequent occurrence and manifests itself in several forms, including (1) small cell carcinoma, (2) carcinoid and carcinoid-like tumors, and (3) conventional adenocarcinoma with focal neuroendocrine differentiation. This latter pattern is the most common, and there is evidence that all or nearly all prostatic adenocarcinomas show at least some focal neuroendocrine differentiation. A review of the world's literature on this topic is included. Neuroendocrine differentiation generally portends a poorer prognosis but may also correlate directly with the grade. There is some evidence to suggest that neoplastic cells with neuroendocrine differentiation are resistant to hormonal therapy. Eutopic and ectopic hormone production may allow screening for prostatic carcinoma and/or monitoring for recurrence of prostatic carcinomas. Finally, the more basic implications of endocrine-paracrine cells and neuroendocrine differentiation are speculated on in reference to prostatic carcinogenesis and autocrine/paracrine tumor growth factor activity.

We studied the regulation of the secretion of CT and CGRP by chromogranin A (CgA)-derived peptides in a human lung tumor cell line. The amino-terminal peptide of CgA, CgA1-40, stimulated the secretion of CGRP and inhibited the secretion of CT; both effects occurred in a dose-dependent manner. These studies demonstrate a differential effect of a CgA-derived peptide on two products of the CT gene, CT itself and CGRP. CgA may be processed at its multiple dibasic sites to peptides that specifically regulate the secretion of its coresident hormones, in this case two calcitonin gene products that are present in the same secretory vesicle. This novel mechanism represents a new pathway for the control of calcium regulating hormones.

We have studied the pattern of chromogranin A (CgA)-related species in different human endocrine cells that produce CgA and also express the calcitonin gene. Antibodies against CgA peptides that span its linear sequence were used in Western analysis of cell lines derived from medullary thyroid carcinoma (MTC), small cell lung cancers (SCLC), epidermoid cell lung cancer (ECLC) and a pulmonary carcinoid tumor (CRND). Each of the cell lines demonstrated a distinct pattern of CgA-related species. Gel filtration studies also revealed multiple and different forms of immunoreactive CgA in the cell lines. Although proteolysis may contribute to our results, these observations suggest that native CgA is processed to smaller species in a tissue-specific pattern by different endocrine cells. More conclusive studies, however, are necessary to establish that cell processing leads to the specific CgA moieties that we have observed.

The chromogranins/secretogranins are a family of acidic, soluble proteins with widespread neuroendocrine distribution in secretory vesicles. Although the precise function of the chromogranins remains elusive, knowledge of their structure, distribution, and potential intracellular and extracellular roles, especially that of chromogranin A, has greatly expanded during recent years. Chromogranin A is coreleased with catecholamines by exocytosis from vesicles in the adrenal medulla and sympathetic nerve endings. Thus, measurement of its circulating concentration by radioimmunoassay may be a useful probe of exocytotic sympathoadrenal activity in humans, under both physiological and pathological conditions. Here, we explore the storage, structure, and function of chromogranin A, and parameters that influence its circulating levels. We have also measured plasma chromogranin A concentrations in different groups of patients with hypertension, including those with pheochromocytoma.

The effects of the hypothalamic hormones, thyrotropin-releasing hormone (TRH), and somatostatin (SRIH), and of phorbol 12-myristate 13-acetate (PMA) on PRL and GH secretion and messenger RNA (mRNA) levels were analyzed in 10 GH and/or PRL producing adenomas after culturing the tumor cells in the presence of these secretagogues for 7 days. The expression of chromogranin A and B mRNAs was also examined. All four of the clinically diagnosed GH adenomas expressed or secreted both GH and PRL while four of six clinically diagnosed prolactinomas produced or secreted both PRL and GH. Prolactinomas had less than 10% of tumor cells expressing chromogranin A mRNA while more than 40% of the adenoma cells expressed chromogranin B mRNA. TRH stimulated PRL secretion and increased PRL mRNA levels while SRIH decreased GH secretion and mRNA expression in some cases. Unexpectedly, PMA stimulated PRL mRNA levels four- to sevenfold above control levels in two adenomas and generally stimulated chromogranin A and B mRNA expression but not GH mRNA, as determined by Northern hybridization and in situ hybridization analyses.These results indicate that cultured prolactinoma cells express significantly more chromogranin B mRNA than chromogranin A mRNA, and that PMA increases PRL mRNA expression in some prolactinomas, although the effect of PMA on various adenomas reflects the heterogeneity of these tumors with respect to protein kinase C stimulation.