Skip to main content

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

A Commentary to this article was published on 19 November 2010

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.

This is a preview of subscription content, access via your institution.

References

  • Banks P, Helle K (1965) The release of protein from the stimulated adrenal medulla. Biochem J 97:40C–41C

    CAS  PubMed  Google Scholar 

  • Bordi C, Yu JY, Baggi MT, Davoli C, Pilato FP, Baruzzi G, Gardini G, Zamboni G, Franzin G, Papotti M, Bussolati G (1991) Gastric carcinoids and their precursor lesions. A histologic and immunohistochemical study of 23 cases. Cancer 67:663–672

    CAS  Article  PubMed  Google Scholar 

  • Cunningham RT, Pogue KM, Curry WJ, Johnston CF, Sloan JM, Buchanan KD (1999) Immunostaining for vasostatin I distinguishes between ileal and lung carcinoids. J Pathol 187:321–325

    CAS  Article  PubMed  Google Scholar 

  • Fahrenkamp AG, Wibbeke C, Winde G, Ofner D, Böcker W, Fischer-Colbrie R, Schmid KW (1995) Immunohistochemical distribution of chromogranins A and B and secretogranin II in neuroendocrine tumours of the gastrointestinal tract. Virchows Arch 426:361–367

    CAS  Article  PubMed  Google Scholar 

  • Feldman SA, Eiden LE (2003) The chromogranins: their roles in secretion from neuroendocrine cells and as markers for neuroendocrine neoplasia. Endocr Pathol 14:3–23

    CAS  Article  PubMed  Google Scholar 

  • Fischer-Colbrie R (1987) Chromogranins A, B and C: widespread constituents of secretory vesicles. Ann NY Acad Sci 493:120–134

    CAS  Article  PubMed  Google Scholar 

  • Fischer-Colbrie R, Laslop A, Kirchmair R (1995) Secretogranin II: molecular properties, regulation of biosynthesis and processing to the neuropeptide secretoneurin. Prog Neurobiol 46:49–70

    CAS  Article  PubMed  Google Scholar 

  • Galindo E, Rill A, Bader MF, Aunis D (1991) Chromostatin, a 20-amino acid peptide derived from chromogranin A, inhibits chromaffin cell secretion. Proc Natl Acad Sci USA 88:1426–1430

    CAS  Article  PubMed  Google Scholar 

  • Guillemot J, Anouar Y, Montero-Hadjadje M, Grouzmann E, Grumolato L, Roshmaninho-Salgado J, Turquier V, Duparc C, Lefebvre H, Plouin PF, Klein M, Muresan M, Chow BK, Vaudry H, Yon L (2006) Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma. Int J Cancer 118:2003–2012

    CAS  Article  PubMed  Google Scholar 

  • Helle KB (1966) Some chemical and physical properties of the soluble protein fraction of bovine adrenal chromaffin granules. Mol Pharmacol 2:298–310

    CAS  PubMed  Google Scholar 

  • Helle KB (2004) The granin family of uniquely acidic proteins of the diffuse neuroendocrine system: comparative and functional aspects. Biol Rev Camb Philos Soc 79:769–794

    Article  PubMed  Google Scholar 

  • Helle KB, Corti A, Metz-Boutigue MH, Tota B (2007) The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. Cell Mol Life Sci 64:2863–2886

    CAS  Article  PubMed  Google Scholar 

  • Hsi KL, Seidah NG, De Serres G, Chrétien M (1982) Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide. Homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60. FEBS Lett 147:261–266

    CAS  Article  PubMed  Google Scholar 

  • Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R (1997) Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 272:11657–11662

    CAS  Article  PubMed  Google Scholar 

  • Jin L, Zhang S, Bayliss J, Scheithauer B, Qian X, Kobayashi I, Stridsberg M, Lloyd RV (2003) Chromogranin a processing in human pituitary adenomas and carcinomas: analysis with region-specific antibodies. Endocr Pathol 14:37–48

    CAS  Article  PubMed  Google Scholar 

  • Krüger PG, Mahata SK, Helle KB (2003) Catestatin (CgA344–364) stimulates rat mast cell release of histamine in a manner comparable to mastoparan and other cationic charged neuropeptides. Regul Pept 114:29–35

    Article  PubMed  Google Scholar 

  • Lee RW, Huttner WB (1983) Tyrosine-O-sulfated proteins of PC12 pheochromocytoma cells and their sulfation by a tyrosylprotein sulfotransferase. J Biol Chem 258:11326–11334

    CAS  PubMed  Google Scholar 

  • Martens GJM (1988) Cloning and sequence analysis of human pituitary cDNA encoding the novel polypeptide 7B2. FEBS Lett 234:160–164

    CAS  Article  PubMed  Google Scholar 

  • O’Connor DT, Deftos LJ (1986) Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 314:1145–1151

    Article  PubMed  Google Scholar 

  • Öberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn MH, Välimäki M, Nordic NE Tumour Group (2004) Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I—general overview. Acta Oncol 43:617–625

    Article  PubMed  Google Scholar 

  • Ottiger HP, Battenberg EF, Tsou AP, Bloom FE, Sutcliffe JG (1990) 1B1075: a brain- and pituitary-specific mRNA that encodes a novel chromogranin/secretogranin-like component of intracellular vesicles. J Neurosci 10:3135–3147

    CAS  PubMed  Google Scholar 

  • Portela-Gomes GM (2000) Chromogranin A immunoreactivity in neuroendocrine cells in the human gastrointestinal tract and pancreas. Adv Exp Med Biol 482:193–204

    CAS  Article  PubMed  Google Scholar 

  • Portela-Gomes GM, Stridsberg M (2001) Selective processing of chromogranin A in the different islet cells in human pancreas. J Histochem Cytochem 49:483–490

    CAS  PubMed  Google Scholar 

  • Portela-Gomes GM, Stridsberg M (2002a) Region-specific antibodies to chromogranin B display various immunostaining patterns in human endocrine pancreas. J Histochem Cytochem 50:1023–1030

    CAS  PubMed  Google Scholar 

  • Portela-Gomes GM, Stridsberg M (2002b) Chromogranin A in the human gastrointestinal tract: an immunohistochemical study with region-specific antibodies. J Histochem Cytochem 50:1493–1500

    Google Scholar 

  • Portela-Gomes GM, Stridsberg M, Johansson H, Grimelius L (1997) Complex co-localization of chromogranins and neurohormones in the human gastrointestinal tract. J Histochem Cytochem 45:815–822

    CAS  PubMed  Google Scholar 

  • Portela-Gomes GM, Lukinius A, Grimelius L (2000) Synaptic vesicle protein 2, a new neuroendocrine cell marker. Am J Pathol 157:1299–1303

    CAS  PubMed  Google Scholar 

  • Portela-Gomes GM, Stridsberg M, Johansson H, Wilander E, Grimelius L (2001) Chromogranin A in human neuroendocrine tumors: an immunohistochemical study with region-specific antibodies. Am J Surg Pathol 25:1261–1267

    Article  Google Scholar 

  • Portela-Gomes GM, Stridsberg M, Grimelius L, Falkmer UG, Falkmer S (2004) Expression of chromogranins A, B, and C (secretogranin II) in human adrenal medulla and in benign and malignant pheochromocytomas. An immunohistochemical study with region-specific antibodies. APMIS 112:663–673

    CAS  Article  PubMed  Google Scholar 

  • Portela-Gomes GM, Grimelius L, Stridsberg M, Puppa G, Bresaola E, Viale G, Pelosi G (2005) Expression of amino acid sequences of the chromogranin A molecule and synaptic vesicle protein 2 in neuroendocrine tumours of the lung. Virchows Arch 446:604–612

    CAS  Article  PubMed  Google Scholar 

  • Portela-Gomes GM, Grimelius L, Stridsberg M (2010a) Secretogranin III in human neuroendocrine tumours. A comparative immunohistochemical study with chromogranins A and B and secretogranin II. Regul Pept. doi:10.1016/j.regpep.2010.06.002

  • Portela-Gomes GM, Grimelius L, Wilander E, Stridsberg M (2010b) Granins and granin-related peptides in neuroendocrine tumours. Regul Pept. doi:10.1016/j.regpep.2010.02.011

  • Rosa P, Zanini A (1981) Characterization of adenohypophysial polypeptides by two-dimensional gel electrophoresis. II. Sulfated and glycosylated polypeptides. Mol Cell Endocrinol 24:181–193

    CAS  Article  PubMed  Google Scholar 

  • Solcia E, Kloppel G, Sobin LH (2000)World Health Organization international histological classification of tumors. Histological typing of endocrine tumors. Springer, Berlin, pp 56–68

  • Sonnleitner-Wittauer U, Hacker GW, Frick J, Dietze D, Sandelin K, Portela-Gomes G, Johansson H, Grimelius L (1996) Regulatory peptides and other markers in human parathyroid adenomas and carcinomas investigated by immunogold-silver staining. Cell Vis 3:27–34

    CAS  Google Scholar 

  • Srikanta S, Krisch K, Eisenbarth GS (1986) Islet cell proteins defined by monoclonal islet cell antibody HISL-19. Diabetes 35:300–305

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M (2000) Measurements of chromogranins and chromogranin-related peptides by immunological methods. Adv Exp Med Biol 482:319–327

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Öberg K, Li Q, Engström U, Lundqvist G (1995) 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. J Endocrinol 144:49–59

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Eriksson B, Oberg K, Janson ET (2004) A panel of 11 region-specific radioimmunoassays for measurements of human chromogranin A. Regul Pept 117:219–227

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Eriksson B, Oberg K, Janson ET (2005) A panel of 13 region-specific radioimmunoassays for measurements of human chromogranin B. Regul Pept 125:193–199

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Eriksson B, Fellstrom B, Kristiansson G, Tiensuu Janson E (2007) Measurements of chromogranin B can serve as a complement to chromogranin A. Regul Pept 139:80–83

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Eriksson B, Janson ET (2008a) Measurements of secretogranins II, III, V and proconvertases 1/3 and 2 in plasma from patients with neuroendocrine tumours. Regul Pept 148:95–98

    CAS  Article  PubMed  Google Scholar 

  • Stridsberg M, Grimelius L, Portela-Gomes GM (2008b) Immunohistochemical staining of human islet cells with region-specific antibodies against secretogranins II and III. J Anat 212:229–234

    CAS  Article  PubMed  Google Scholar 

  • Strub JM, Goumon Y, Lugardon K, Capon C, Lopez M, Moniatte M, Dorsselaer AV, Aunis D, Metz-Boutigue MH (1996) Antibacterial activity of glycosylated and phosphorylated chromogranin A-derived peptide 173–194 from bovine adrenal medullary chromaffin granules. J Biol Chem 45:28533–28540

    Google Scholar 

  • Tartaglia A, Portela-Gomes GM, Öberg K, Vezzadini P, Foschini MP, Stridsberg M (2006) Chromogranin A in gastric neuroendocrine tumours: an immunohistochemical and biochemical study with region-specific antibodies. Virchows Arch 448:399–406

    CAS  Article  PubMed  Google Scholar 

  • Thompson LDR (2002) Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from malignant neoplasms. A clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26:551–566

    Article  PubMed  Google Scholar 

  • Twardzik DR, Brown JP, Ranchalis JE, Todaro GJ, Moss B (1985) Vaccinia virus-infected cells release a novel polypeptide functionally related to transforming and epidermal growth factors. Proc Natl Acad Sci USA 82:5300–5304

    CAS  Article  PubMed  Google Scholar 

  • Watkinson A, Jönsson AC, Davison M, Young J, Lee CM, Moore S, Dockray GJ (1991) Heterogeneity of chromogranin A-derived peptides in bovine gut, pancreas and adrenal medulla. Biochem J 276:471–479

    CAS  PubMed  Google Scholar 

  • Weiler R, Fischer-Colbrie R, Schmid KW, Feichtinger H, Bussolati G, Grimelius L, Krisch K, Kerl H, O’Connor D, Winkler H (1988) Immunological studies on the occurrence and properties of chromogranin A and B and secretogranin II in endocrine tumors. Am J Surg Pathol 12:877–884

    CAS  Article  PubMed  Google Scholar 

  • Winkler H, Laslop A, Leitner B, Weiss C (1998) The secretory cocktail of adrenergic large dense-core vesicles: the functional role of the chromogranins. Adv Pharmacol 42:257–259

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Guida M. Portela-Gomes.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Portela-Gomes, G.M., Grimelius, L. & Stridsberg, M. Immunohistochemical and Biochemical Studies with Region-Specific Antibodies to Chromogranins A and B and Secretogranins II and III in Neuroendocrine Tumors. Cell Mol Neurobiol 30, 1147–1153 (2010). https://doi.org/10.1007/s10571-010-9585-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-010-9585-x

Keywords

  • Chromogranin A
  • Chromogranin B
  • Secretogranin II
  • Secretogranin III
  • Neuroendocrine tumor
  • Immunohistochemistry
  • Plasma concentration measurements