Cellular and Molecular Neurobiology

, Volume 30, Issue 8, pp 1163–1170 | Cite as

Chromogranin A and the Tumor Microenvironment

  • Angelo Corti
Review Paper


Chromogranin A (CgA) is an acidic glycoprotein belonging to a family of regulated secretory proteins stored in the dense core granules of the adrenal medulla and of many other neuroendocrine cells and neurons. This protein is frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors. Circulating CgA is also increased in patients with other diseases, including subpopulations of patients with non-neuroendocrine tumors, with important prognostic implications. A growing body of evidence suggests that CgA is more than a diagnostic/prognostic marker for cancer patients. Indeed, results of in vitro experiments and in vivo studies in animal models suggest that this protein and its fragments can affect several elements of the tumor microenvironment, including fibroblasts and endothelial cells. In this article, recent findings implicating CgA as a modulator of the tumor microenvironment and suggesting that abnormal secretion of CgA could play important roles in tumor progression and response to therapy in cancer patients are reviewed and discussed.


Chromogranin A Neuroendocrine tumor Tumor stroma Cell adhesion Endothelial cells Fibroblasts Tumor necrosis factor Vascular leakage VEGF Angiogenesis 



Chromogranin A


Tumor necrosis factor alpha


Vascular endothelial growth factor


Recombinant vasostatin-I



This study was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), Alleanza Contro il Cancro (ACC), and FIRB (Italy).


  1. Aderka D (1996) The potential biological and clinical significance of the soluble tumor necrosis factor receptors. Cytokine Growth Factor Rev 7:231–240CrossRefPubMedGoogle Scholar
  2. Anderson GM, Nakada MT, DeWitte M (2004) Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer. Curr Opin Pharmacol 4:314–320CrossRefPubMedGoogle Scholar
  3. Angeletti RH, Aardal S, Serck-Hanssen G, Gee P, Helle KB (1994) Vasoinhibitory activity of synthetic peptides from the amino terminus of chromogranin A. Acta Physiol Scand 152:11–19CrossRefPubMedGoogle Scholar
  4. Belloni D, Scabini S, Foglieni C, Veschini L, Giazzon A, Colombo B, Fulgenzi A, Helle KB, Ferrero ME, Corti A, Ferrero E (2007) The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration. FASEB J 21:3052–3062CrossRefPubMedGoogle Scholar
  5. Blois A, Holmsen H, Martino G, Corti A, Metz-Boutigue MH, Helle KB (2006a) Interactions of chromogranin A-derived vasostatins and monolayers of phosphatidylserine, phosphatidylcholine and phosphatidylethanolamine. Regul Pept 134:30–37CrossRefPubMedGoogle Scholar
  6. Blois A, Srebro B, Mandalà M, Corti A, Helle KB, Serck-Hanssen G (2006b) The chromogranin A peptide vasostatin-I inhibits gap formation and signal transduction mediated by inflammatory agents in cultured bovine pulmonary and coronary arterial endothelial cells. Regul Pept 135:78–84CrossRefPubMedGoogle Scholar
  7. Bretscher A, Edwards K, Fehon RG (2002) ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3:586–599CrossRefPubMedGoogle Scholar
  8. Ceconi C, Ferrari R, Bachetti T, Opasich C, Volterrani M, Colombo B, Parrinello G, Corti A (2002) Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality. Eur Heart J 23:967–974CrossRefPubMedGoogle Scholar
  9. Ciesielski-Treska J, Ulrich G, Taupenot L, Chasserot-Golaz S, Corti A, Aunis D, Bader MF (1998) Chromogranin A induces a neurotoxic phenotype in brain microglial cells. J Biol Chem 273:14339–14346CrossRefPubMedGoogle Scholar
  10. Colombo B, Curnis F, Foglieni C, Monno A, Arrigoni G, Corti A (2002a) Chromogranin A expression in neoplastic cells affects tumor growth and morphogenesis in mouse models. Cancer Res 62:941–946PubMedGoogle Scholar
  11. Colombo B, Longhi R, Marinzi C, Magni F, Cattaneo A, Yoo SH, Curnis F, Corti A (2002b) Cleavage of chromogranin A N-terminal domain by plasmin provides a new mechanism for regulating cell adhesion. J Biol Chem 277:45911–45919CrossRefPubMedGoogle Scholar
  12. Corti A, Ferrero E (2004) Chromogranin A: more than a marker for tumor diagnosis and prognosis. Curr Med Chem—Immunol Endocr Metab Agents 4:161–167CrossRefGoogle Scholar
  13. Corti A, Gasparri A, Chen FX, Pelagi M, Brandazza A, Sidoli A, Siccardi AG (1996) Characterisation of circulating chromogranin A in human cancer patients. Br J Cancer 73:924–932PubMedGoogle Scholar
  14. Corti A, Ferrari R, Ceconi C (2000) Chromogranin A and tumor necrosis factor alpha in heart failure. Adv Exp Med Biol 482:351–359CrossRefPubMedGoogle Scholar
  15. Deftos LJ (1991) Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumor marker. Endocr Rev 12:181–187CrossRefPubMedGoogle Scholar
  16. Di Comite G, Rossi CM, Marinosci A, Lolmede K, Baldissera E, Aiello P, Mueller RB, Herrmann M, Voll RE, Rovere-Querini P, Sabbadini MG, Corti A, Manfredi AA (2009) Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation. J Leukoc Biol 85:81–87CrossRefPubMedGoogle Scholar
  17. Dondossola E, Gasparri A, Bachi A, Longhi R, Metz-Boutigue MH, Tota B, Helle KB, Curnis F, Corti A (2010) Role of vasostatin-1 C-terminal region in fibroblast cell adhesion. Cell Mol Life Sci 12:2107–2118CrossRefGoogle Scholar
  18. Ferrero E, Scabini S, Magni E, Foglieni C, Belloni D, Colombo B, Curnis F, Villa A, Ferrero ME, Corti A (2004) Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage. FASEB J 20:20Google Scholar
  19. Fiers W (1995) Biologic therapy with TNF: preclinical studies. In: De Vita V, Hellman S, Rosenberg S (eds) Biologic therapy of cancer: principles and practice. J.B. Lippincott Company, Philadelphia, pp 295–327Google Scholar
  20. Gasparri A, Sidoli A, Sanchez LP, Longhi R, Siccardi AG, Marchisio PC, Corti A (1997) Chromogranin A fragments modulate cell adhesion. Identification and characterization of a pro-adhesive domain. J Biol Chem 272:20835–20843CrossRefPubMedGoogle Scholar
  21. Giusti M, Sidoti M, Augeri C, Rabitti C, Minuto F (2004) Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man. Eur J Endocrinol 150:299–303CrossRefPubMedGoogle Scholar
  22. Gregorc V, Spreafico A, Floriani I, Colombo B, Ludovini V, Pistola L, Bellezza G, Vigano MG, Villa E, Corti A (2007) Prognostic value of circulating chromogranin A and soluble tumor necrosis factor receptors in advanced nonsmall cell lung cancer. Cancer 110:845–853CrossRefPubMedGoogle Scholar
  23. Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268PubMedGoogle Scholar
  24. 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 64:2863–2886CrossRefPubMedGoogle Scholar
  25. Helpap B, Kollermann J (2001) Immunohistochemical analysis of the proliferative activity of neuroendocrine tumors from various organs. Are there indications for a neuroendocrine tumor-carcinoma sequence? Virchows Arch 438:86–91CrossRefPubMedGoogle Scholar
  26. Iyoda A, Hiroshima K, Toyozaki T, Haga Y, Fujisawa T, Ohwada H (2001) Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 91:1992–2000CrossRefPubMedGoogle Scholar
  27. Janson ET, Holmberg L, Stridsberg M, Eriksson B, Theodorsson E, Wilander E, Oberg K (1997) Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 8:685–690CrossRefPubMedGoogle Scholar
  28. Kimura N, Yoshida R, Shiraishi S, Pilichowska M, Ohuchi N (2002) Chromogranin A and chromogranin B in noninvasive and invasive breast carcinoma. Endocr Pathol 13:117–122CrossRefPubMedGoogle Scholar
  29. Kramer MD, Reinartz J, Brunner G, Schirrmacher V (1994) Plasmin in pericellular proteolysis and cellular invasion. Invasion Metastasis 14:210–222PubMedGoogle Scholar
  30. Lugardon K, Raffner R, Goumon Y, Corti A, Delmas A, Bulet P, Aunis D, Metz-Boutigue MH (2000) Antibacterial and antifungal activities of vasostatin-1, the N-terminal fragment of chromogranin A. J Biol Chem 275:10745–10753CrossRefPubMedGoogle Scholar
  31. Lugardon K, Chasserot-Golaz S, Kieffer AE, Maget-Dana R, Nullans G, Kieffer B, Aunis D, Metz-Boutigue MH (2001) Structural and biological characterization of chromofungin, the antifungal chromogranin A-(47–66)-derived peptide. J Biol Chem 276:35875–35882CrossRefPubMedGoogle Scholar
  32. Mahata SK, Mahata M, Fung MM, O’Connor DT (2010) Catestatin: a multifunctional peptide from chromogranin A. Regul Pept 162:33–43CrossRefPubMedGoogle Scholar
  33. Mandalà M, Stridsberg M, Helle KB, Serck-Hanssen G (2000) Endothelial handling of chromogranin A. Adv Exp Med Biol 482:167–178CrossRefPubMedGoogle Scholar
  34. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583–592CrossRefPubMedGoogle Scholar
  35. O’Connor DT, Deftos LJ (1986) Secretion of chromogranin A by peptide-producing endocrine neoplasms. New Engl J Med 314:1145–1151CrossRefPubMedGoogle Scholar
  36. Pieroni M, Corti A, Tota B, Curnis F, Angelone T, Colombo B, Cerra MC, Bellocci F, Crea F, Maseri A (2007) Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function. Eur Heart J 28:1117–1127CrossRefPubMedGoogle Scholar
  37. Portela-Gomes GM, Grimelius L, Wilander E, Stridsberg M (2010) Granins and granin-related peptides in neuroendocrine tumours. Regul Pept (in press)Google Scholar
  38. Ratti S, Curnis F, Longhi R, Colombo B, Gasparri A, Magni F, Manera E, Metz-Boutigue MH, Corti A (2000) Structure-activity relationships of chromogranin A in cell adhesion. Identification and characterization of an adhesion site for fibroblasts and smooth muscle cells. J Biol Chem 275:29257–29263CrossRefPubMedGoogle Scholar
  39. Russell J, Gee P, Liu SM, Angeletti RH (1994) Inhibition of parathyroid hormone secretion by amino-terminal chromogranin peptides. Endocrinology 135:337–342CrossRefPubMedGoogle Scholar
  40. Simon JP, Aunis D (1989) Biochemistry of the chromogranin A protein family. Biochem J 262:1–13PubMedGoogle Scholar
  41. Stridsberg M, Angeletti RH, Helle KB (2000) Characterisation of N-terminal chromogranin A and chromogranin B in mammals by region-specific radioimmunoassays and chromatographic separation methods. J Endocrinol 165:703–714CrossRefPubMedGoogle Scholar
  42. Szlosarek PW, Balkwill FR (2003) Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol 4:565–573CrossRefPubMedGoogle Scholar
  43. Taupenot L, Harper KL, O’Connor DT (2003) The chromogranin-secretogranin family. New Engl J Med 348:1134–1149CrossRefPubMedGoogle Scholar
  44. Tota B, Angelone T, Mazza R, Cerra MC (2008) The chromogranin A-derived vasostatins: new players in the endocrine heart. Curr Med Chem 15:1444–1451CrossRefPubMedGoogle Scholar
  45. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454CrossRefPubMedGoogle Scholar
  46. Turquier V, Vaudry H, Jegou S, Anouar Y (1999) Frog chromogranin A messenger ribonucleic acid encodes three highly conserved peptides. Coordinate regulation of proopiomelanocortin and chromogranin A gene expression in the pars intermedia of the pituitary during background color adaptation. Endocrinology 140:4104–4112CrossRefPubMedGoogle Scholar
  47. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995PubMedGoogle Scholar
  48. Young RH, Srigley JR, Amin MB, Ulbright TM, Cubilla AL (2000) Carcinoma of the prostate gland (excluding unusual variants and secondary carcinomas). In: Rosai J, Sobin LH (eds) Atlas of tumor pathology, vol 28. Armed Forces Institute of Pathology, Washington, DC, pp 111–216Google Scholar
  49. Zhang K, Rao F, Wen G, Salem RM, Vaingankar S, Mahata M, Mahapatra NR, Lillie EO, Cadman PE, Friese RS, Hamilton BA, Hook VY, Mahata SK, Taupenot L, O’Connor DT (2006) Catecholamine storage vesicles and the metabolic syndrome: the role of the chromogranin A fragment pancreastatin. Diabetes Obes Metab 8:621–633CrossRefPubMedGoogle Scholar
  50. Zhang D, Shooshtarizadeh P, Laventie BJ, Colin DA, Chich JF, Vidic J, de Barry J, Chasserot-Golaz S, Delalande F, Van Dorsselaer A, Schneider F, Helle K, Aunis D, Prevost G, Metz-Boutigue MH (2009) Two chromogranin A-derived peptides induce calcium entry in human neutrophils by calmodulin-regulated calcium independent phospholipase A2. PLoS One 4:e4501CrossRefPubMedGoogle Scholar
  51. Ziegler MG, Kennedy B, Morrissey E, O’Connor DT (1990) Norepinephrine clearance, chromogranin A and dopamine beta hydroxylase in renal failure. Kidney Int 37:1357–1362CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Molecular Oncology and IIT Network Research Unit of Molecular NeuroscienceSan Raffaele Scientific InstituteMilanItaly

Personalised recommendations