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. 2010 Nov 3;30(8):1147–1153. doi: 10.1007/s10571-010-9585-x

Immunohistochemical and Biochemical Studies with Region-Specific Antibodies to Chromogranins A and B and Secretogranins II and III in Neuroendocrine Tumors

Guida M Portela-Gomes 1,4,✉, Lars Grimelius 2, Mats Stridsberg 3
PMCID: PMC11498889  PMID: 21046454

Abstract

This short review deals with our investigations in neuroendocrine tumors (NETs) with antibodies against defined epitopes of chromogranins (Cgs) A and B and secretogranins (Sgs) II and III. The immunohistochemical expression of different epitopes of the granin family of proteins varies in NE cells in normal human endocrine and non-endocrine organs and in NETs, suggesting post-translational processing. In most NETs one or more epitopes of the granins were lacking, but variations in the expression pattern occurred both in benign and malignant NETs. A few epitopes displayed patterns that may be valuable in differentiating between benign and malignant NET types, e.g., well-differentiated NET types expressed more CgA epitopes than the poorly differentiated ones and C-terminal secretoneurin visualized a cell type related to malignancy in pheochromocytomas. Plasma concentrations of different epitopes of CgA and CgB varied. In patients suffering from carcinoid tumors or endocrine pancreatic tumors the highest concentrations were found with epitopes from the mid-portion of CgA. For CgB the highest plasma concentrations were recorded for the epitope 439–451. Measurements of SgII showed that patients with endocrine pancreatic tumors had higher concentrations than patients with carcinoid tumors or pheochromocytomas. SgIII was not detectable in patients with NETs.

Keywords: Chromogranin A, Chromogranin B, Secretogranin II, Secretogranin III, Neuroendocrine tumor, Immunohistochemistry, Plasma concentration measurements

Introduction

The granin family comprises the chromogranins (Cgs) and secretogranins (Sgs) and consists at present of eight members—CgA (Banks and Helle 1965; Helle 1966), CgB (initially called SgI; Lee and Huttner 1983), SgII (initially called CgC; Rosa and Zanini 1981; Fischer-Colbrie et al. 1995), SgIII (Ottiger et al. 1990), SgIV (human islet cell (HISL-19) antigen; Srikanta et al. 1986), SgV (neuroendocrine (NE) secretory protein 7B2; Hsi et al. 1982; Martens 1988), SgVI (NE secretory protein (NESP)-55; Ischia et al. 1997) and SgVII (vaccinia growth factor (VGF) or nerve growth factor inducible protein VGF; Twardzik et al. 1985) (cf. Helle 2004).

Granins are single chain acidic glycoproteins, the shortest is SgV (185 amino acids), the longest CgB (657 amino acids). Cgs differ from Sgs by having an N-terminal hydrophobic disulphide-bonded loop, which the latter lack. All granins contain numerous pairs of basic amino acids and monobasic residues that are potential sites for cleavage by several endogenous proteases, such as prohormone convertases, giving rise to smaller peptides, some have been shown to possess biological activity (cf. Helle et al. 2007).

It is well known that granins are widely expressed in the diffuse NE cell system and in NE tumors (NETs) (cf. Fischer-Colbrie 1987; Feldman and Eiden 2003). In the NE cells, granins are stored in large membrane-bound dense core vesicles, usually called secretory granules, where they are stored together with prohormones and hormones, hormone processing enzymes, amines, nucleotides, calcium, and magnesium. Granins and hormones are released by exocytosis upon stimulation. Granins are probably of great importance as they may account for up to 80% of the core proteins.

NETs are presently classified by the World Health Organization system, according to their localization and degree of differentiation (Solcia et al. 2000). A subset of NETs is functional, having clinical symptoms depending on their hormone production, but there are non-functional NETs that lack endocrine symptoms (Öberg et al. 2004). Furthermore, the differential diagnosis between NETs and non-NETs has important consequences for treatment and prognosis. The cells and the cellular patterns may be similar. Therefore, sensitive general markers are needed for the identification of NETs in addition to immunohistochemical stainings for specific hormones that may be produced by the heterogeneous group of NETs.

CgA has an important role both in immunohistochemical and biochemical analysis to identify NETs. Other members of the granin family are less investigated, however, CgB has been used in a limited number of studies.

This short review is mainly based upon our own immunohistochemical and biochemical investigations of NETs with antibodies raised against defined epitopes of Cgs A and B, and Sgs II and III (Table 1). These studies aimed to investigate possible marker functions for the immunohistochemical detection and plasma determination of granins and granin-derived peptides. It must be noted that the antibodies have not been characterized on whether they bind only to processed parts of the molecules or only to unprocessed sequences or both.

Table 1.

Amino acid sequences of the human peptides that were used for raising the granin region-specific antibodies

Antibody directed to amino acid sequence Corresponding peptide
CgA
 LK2H10 250–284a N-terminal pancreastatin
 1–17 N-terminal vasostatins
 17–38 Disulfide bridge part of vasostatins
 63–76 C-terminal vasostatin-I
 100–113 C-terminal vasostatin-II
 116–130 N-terminal chromostatin
 176–195 Chromacin
 238–247
 284–301 C-terminal pancreastatin
 324–337 WE-14
 361–372 C-terminal catestatin (N-terminal parastatin)
 375–384 Mid-parastatin, GE-25
 411–424 C-terminal parastatin
CgB
 1–16
 16–37
 153–167
 244–255
 259–270
 312–331
 406–417
 420–432 N-terminal GAWK
 439–451 C-terminal GAWK
 506–517
 542–552
 555–565 C-terminal PE-11
 568–577 N-terminal chrombacin
 580–593 Mid-chrombacin, BAM-1745
 622–632 C-terminal chrombacin, mid-CCB, secretolytin (614–626)
 647–657 C-terminal CCB
SgII
 154–165 N-terminal secretoneurin
 172–186 C-terminal secretoneurin
 223–249 Part of C-terminal EM-66
SgIII
 141–156
 348–361
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All antibodies were raised in rabbits, with the exception of the mouse monoclonal antibody, clone LK2H10 (Boehringer-Mannheim; Mannheim, Germany). Cg chromogranin, Sg secretogranin

aPortela-Gomes and Stridsberg (2001)

Immunohistochemical Studies

The distribution of different epitopes of Cgs A (n = 13) and B (n = 16) and Sgs II (n = 3) and III (n = 1) (Table 1) has been systematically studied in various normal NE cell types in different endocrine and non-endocrine organs, particularly in the gastro-entero-pancreatic system. Various epitopes were expressed to a varying extent in different NE cell types, indicating cell-specific cleavage of the granin molecules (Portela-Gomes 2000; Portela-Gomes et al. 1997, 2004, 2005; Portela-Gomes and Stridsberg 2001, 2002a, b; Stridsberg et al. 2008b). The results of the immunohistochemical studies were in accordance with biochemical reports indicating a tissue specific posttranslational processing of granins (Watkinson et al. 1991; Winkler et al. 1998, cf. Helle et al. 2007).

The specificity of the antibodies has been carefully characterized immunohistochemically by neutralization tests performed with the peptides used for immunization, in order to exclude crossreactivity among the region-specific antibodies of each granin, as well as between these and those of the other granins, insulin, glucagon, somatostatin (amino acid sequence 1–14), and pancreatic polypeptide.

Therefore, the immunohistochemical demonstration of the granin epitopes indicates their existence, or availability, but not if they are separate proteins or a part of a larger molecule. The observed variations in the number of immunoreactive cells of a given granin epitope may indicate differing degrees of cleavage of the granin molecules.

The absence of a number of available epitopes of the granin molecule(s) may indicate that the antibody binding epitopes may be masked, by other secretory granule proteins or by the histological processing, thus preventing the immunohistochemical staining; however, our studies indicate that masking is not the sole or entire cause for the varying staining patterns observed. A possible explanation is that there is an abnormal cleavage of the granin molecule on the epitope(s) in question, without cleavage at pairs of basic amino acids or with cleavage with no relationship with the dibasic sites, giving rise to fragments that do not bind to the antibodies used. The lack of immunoreaction may also indicate that the granin epitopes are non-existent, due to lack of translation of these epitopes from the granin mRNA, or else that there is a rapid synthesis and release of peptides, so the granin epitopes are present at such a low concentration that they cannot be detected by the techniques used.

Few studies of the immunohistochemical expression of Cgs A and B and SgII epitopes in NETs have been reported by other authors, who used antibodies raised against individual epitopes and only in a few tumors (cf. Portela-Gomes et al. 2010b). In our studies, we have investigated the immunoreactivity of these granins in various types of human NETs (n = 249) using antibodies raised against several defined regions of the whole human granin molecules (Table 1). These region-specific antibodies were largely chosen on the basis of molecular regions possibly having certain biological functions.

Immunohistochemical differences were found between normal and neoplastic cells, where normal cells contained more molecular regions of Cgs A and B and of SgII than the neoplastic cells. These findings suggested a more extensive posttranslational processing of the granin molecules in neoplastic NE cells compared with the normal NE cells.

Only a few NETs expressed immunohistochemically all examined epitopes of CgA and B and SgII, but variations in the expression pattern of the granin molecular regions were found within a tumor type and also within one and the same tumor. However, a few granin epitopes displayed expression patterns that may be valuable in differentiating between some benign and malignant NET types.

Chromogranin A

In our studies, up to 13 CgA epitopes have been investigated in 249 NETs of various types. As mentioned above, CgA is currently used as a general marker for histopathological diagnosis of NETs, where a monoclonal antibody (clone LK2H10) is widely used. The epitope of this antibody lies in the molecular region 250–284 (N-terminal pancreastatin) (Portela-Gomes and Stridsberg 2001).

Another good general marker for both benign and malignant NETs was the epitope CgA176–195 (chromacin) (Strub et al. 1996), which was the sequence most strongly expressed; the staining results with this antibody agreed well with the findings with the above mentioned commercial monoclonal antibody (cf. Portela-Gomes et al. 2010b).

Our studies showed that CgA expresses more epitopes and often with a stronger intensity in the well-differentiated NET types than in the poorly differentiated ones. One exception regards rectal carcinoid tumors of the L-cell type which contain few or no CgA-immunoreactive cells with the monoclonal antibody widely used in routine histopathology (Portela-Gomes et al. 2000). Other exceptions are insulinomas, where the benign insulinomas expressed fewer epitopes than the malignant ones (Portela-Gomes et al. 2001), and pituitary ACTH-producing tumors, where Jin et al. (2003) reported stronger immunostaining in pituitary ACTH-producing carcinomas than in adenomas.

Different cleavage of a given CgA-derived peptide may also occur in a NET type, e.g., vasostatins in NETs of the lung, where Portela-Gomes et al. (2005) reported that bronchial carcinoid tumors expressed the disulfide bridge part of vasostatin-I (CgA17–38) whereas Cunningham et al. (1999) showed that the C-terminus of vasostatin-I (CgA68–76) was virtually absent in these tumors.

A relationship could not be found between the expression of CgA epitopes and hormone or amine products, with a few exceptions. One exception regards the immunohistochemical expression of the C-terminus of human catestatin (CgA361–372). This epitope was suggested by Tartaglia et al. (2006) as a possible helpful complement in the characterization of ECLomas. Catestatin was the only CgA region observed in all ECLomas types 1 and 3 investigated. It is possible that this epitope is related to a stimulatory effect on histamine release (Krüger et al. 2003) from the histamine-producing ECL neoplastic cells. A further relationship was found between CgA116–130, an antibody that detects part of the N-terminus of chromostatin (Galindo et al. 1991) and gastrin-releasing peptide (GRP) in lung carcinoid tumors (Portela-Gomes et al. 2005). It is of interest to note that somatostatinomas expressed CgA411–424 (C-terminal parastatin) (Portela-Gomes et al. 2001), a finding which agrees with another finding that this epitope was the only present in normal somatostatin cells both in pancreas and gastrointestinal tract (Portela-Gomes and Stridsberg 2001, 2002a, b).

As mentioned earlier, the immunohistochemical demonstration of CgA epitopes indicates their existence, or availability, but not if they are separate proteins or a part of a larger molecule. Furthermore it is unclear if the peptides generated by cleavages of the CgA molecule are released into circulation and have endocrine functions, if they also exert paracrine or autocrine effects or if they are produced in abnormal molecular forms and are non-functional.

Chromogranin B

Our immunohistochemical studies regard the expression of the amino acid sequences CgB244–255 in 76 NETs of several types. This molecular region does not seem to have any functional role, however, our studies in endocrine pancreas suggest a physiological importance of this amino acid sequence, as it is present in all NE cell types, while none of the CgA epitopes was expressed in a similar way. The expression of a further four epitopes were investigated in 29 pheochromocytomas (Portela-Gomes et al. 2004). Our studies show that these CgB epitopes are expressed to various extents in most NET types, where differences in processing of the different CgB epitopes are found in the tumors, as mentioned above. Exceptions are ECLomas and parathyroid adenomas where CgB244–255 was not demonstrated. These tumor types also lacked immunoreactivity in reports by other authors using other CgB epitopes (Weiler et al. 1988; Bordi et al. 1991; Fahrenkamp et al. 1995), but contain CgA epitopes (Portela-Gomes et al. 2000, 2001; Sonnleitner-Wittauer et al. 1996).

It is interesting to note that rectal NETs of the L-cell type, which lack or display a weak CgA immunoreactivity, expressed CgB immunoreactivity with antibodies against CgB244–255 (Portela-Gomes et al. 2010a), which had been previously reported by Fahrenkamp et al. for CgB306–326 (1995).

Secretogranin II and III

Our SgII studies in 76 NETs regard the use of two region-specific antibodies raised against C- and N-terminal secretoneurin (SgII154–165 and SgII175–185) epitopes. Secretoneurin was identified in most NET types, including rectal carcinoids of the L-cell type and gastric ECLomas type 1, but not in parathyroid adenomas.

Our results showed that particularly valuable are C-terminal secretoneurin antibodies which may be helpful in the differential diagnosis between benign and malignant pheochromocytomas; these antibodies visualized distinctly spindle-shaped cells with long processes (Portela-Gomes et al. 2004), cells that had been described in pheochromocytomas as being linked to malignant activity (Thompson 2002).

SgIII348–361 has recently been found in all NET types (n = 47), with exception of parathyroid adenomas (Portela-Gomes et al. 2010a).

Comparisons of the frequency and distribution pattern of CgA, CgB, SgII, and SgIII immunoreactive cells revealed that their expression pattern agreed rather well in most NET types. From our studies, we can conclude that the four granins are widely expressed and broadly co-expressed in NETs. Exceptions were, however, pheochromocytomas, where less SgIII immunoreactive cells were observed, gastric ECLomas which were non-reactive to CgB, and parathyroid adenomas, which were only stained by CgA. In rectal carcinoids, more cells expressed CgB, SgII, and SgIII than CgA. These differences in the expression pattern of granins may be helpful in the histopathological diagnosis of NETs. Furthermore, as mentioned above, particular expression patterns of some granin epitopes may be helpful in distinguishing a few NET types and/or facilitate the differential diagnosis between some benign and malignant NET types.

Biochemical Studies

Plasma measurement of CgA has been used as a general marker for NETs since the middle of the 1980s (O’Connor and Deftos 1986). A limited number of in-house methods for CgA have been published (Stridsberg 2000). They usually used CgA-protein purified from adrenal, pheochromocytoma, or from urine collected from patients with NETs for standard and antibody production. The actual epitopes involved in the antibody binding were usually not characterized. Since the development of commercial kits, CgA has been more widely used. Until recently, no commercial kit for measurements of CgB has been available.

Chromogranin A

The distribution of different epitopes of CgA (n = 12) has been studied in a series of 20 patients with NETs; 10 patients with carcinoid tumors and 10 with pancreatic endocrine tumors (Stridsberg et al. 2004). Plasma concentrations varied between the different epitopes. In general, the highest circulating concentrations were found for the N-terminus of vasostatin-I (CgA1–17), the N-terminal domain of chromostatin (CgA116–130), the C-terminus of pancreastatin (CgA284–301) and WE-14 (CgA324–337). However, only the 284–301 (pancreastatin) and 324–337 (WE-14) epitopes showed correlation to the total CgA concentrations. The plasma concentrations of the other epitopes were generally low, except from the disulfide bridge part of vasostatin-I (CgA17–38), which was increased only in a patient with decreased renal function. Concentrations of intact CgA are usually increased in patient with renal function, but for the region-specific epitopes only the disulfide bridge epitope of vasostatin-I (CgA17–38) was clearly increased.

Chromogranin B

The CgB312–331 has been used for measurements of CgB for several years (Stridsberg et al. 1995). Since CgB is not increased in patients with decreased renal function or during treatments with proton-pump inhibitors this assay has been a valuable complement to CgA measurements. The distribution of different epitopes of CgB (n = 13) was studied in a series of 19 patients with NETs; 9 patients with carcinoid tumors and 10 with pancreatic endocrine tumors (Stridsberg et al. 2005). Only the epitopes CgB1–16, 312–331, 406–417, 420–432, and 439–451 showed clearly measurable concentrations of CgB; the other epitopes showed generally low concentrations. There were correlations between the concentrations of the different CgB assays indicating co-release of the various epitopes. However, only CgB406–417 and 439–451 correlated to intact CgA. There were no obvious associations between concentrations of CgB epitopes and clinical parameters such as decreased renal function or different treatment strategies. The CgB439–451 epitope was found in considerably higher concentrations than any of the other epitopes, including the CgB312–331. Further characterization has identified this assay as a valuable complement to CgA measurements (Stridsberg et al. 2007).

Secretogranin II and III

The distribution of three different epitopes of SgII was studied in nine patients with carcinoid tumors, 10 with pancreatic endocrine tumors, and three with pheochromocytomas (Stridsberg et al. 2008a). With the SgII154–165 assay (N-terminal secretoneurin) 7 out of 10 patients with pancreatic endocrine tumors showed increased plasma concentrations, whereas the SgII172–186 assay (C-terminal secretoneurin) only showed two patients with increased concentrations and the SgII225–242 assay detected three patients. For carcinoid tumors only slightly increased concentration were noted in some of the cases. One of the three patients with pheochromocytoma showed increased concentrations of SgII154–165 and 172–186. From these results, we concluded that SgII154–165 could be a specific marker for endocrine pancreatic tumors, but probably not useful for other NETs. This was opposite to previous results which indicated that SgII187–252 (EM66) was a good marker for pheochromocytomas (Guillemot et al. 2006). None of the patients showed increased concentrations of SgIII141–156.

Concluding Remarks

We have used antibodies raised against various epitopes of Cgs A and B and Sgs II and III in immunohistochemical and biochemical studies of NETs. A variation of immunohistochemical expression and of circulating plasma concentrations of various epitopes was found in different NET types, indicating a specific processing of these granins. A few granin epitopes display immunohistochemical expression patterns that may be of value in the differential diagnosis of NETs and in predicting their biological behavior. Comparing immunohistochemical and biochemical results revealed that antibodies that produced intensive immunostaining usually measured low circulating concentrations and vice versa. This observation indicates that in addition to different processing in different cell types also a different release pattern of granins could be present.

Further studies with region-specific antibodies will likely yield new marker functions for granins that may have histopathological and biochemical value for diagnosis.

Footnotes

A commentary to this article can be found at doi:10.1007/s10571-010-9552-6.

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