Squamous Cell Carcinoma Antigen-Immunoglobulin M (SCCA-IgM) as Biomarker in Liver Disease: Biological Aspects and Clinical Applications

Living reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)

Abstract

Chronic liver diseases and cirrhosis are an increasing cause of morbidity and mortality in Western countries. In particular, liver cirrhosis can be an asymptomatic and silent condition until clinical decompensation occurs, which could lead to organ failure, with a mortality rate up to 30 %. One of the main causes of mortality in patients with cirrhosis is hepatocellular carcinoma, one of the most common fatal cancers worldwide, the 4th one for incidence rate. A high public health priority need is the development of biomarkers to screen for liver disease progression and for early diagnosis of hepatocellular carcinoma development, particularly in the high-risk population represented by patients with cirrhosis. Recently, circulating immune complex squamous cell carcinoma antigen-IgM has shown the ability to identify patients with progressive liver disease and patients at higher risk of hepatocellular carcinoma development. In this chapter, we describe the biochemical and biological features of squamous cell carcinoma antigen and the role of natural IgM to form immune complexes with altered self-antigen during carcinogenesis; we also present the main clinical studies that have investigated this new circulating biomarker in terms of diagnostic and prognostic value in chronic liver disease, liver cirrhosis, and hepatocellular carcinoma.

Keywords

SCCA-IgM Biomarker Cirrhosis Hepatocellular carcinoma HCV Treatment Prognosis 

List of Abbreviations

AFP

Alpha-fetoprotein

AFP-L3

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein

AUROC

Area under receiver operating characteristic

C1q

Complement component 1q

DCP

Des-gamma carboxy-prothrombin

ELISA

Enzyme-linked immunosorbent assay

EMT

Epithelial-mesenchymal transition

EpCam

Epithelial cell adhesion molecule

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

HIF-2α

Hypoxia-inducible factor-2 alpha

IFN-γ

Interferon gamma

IL-6

Interleukin 6

MBL

Mannose-binding lectin

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

NF-kB

Nuclear factor-kappa light-chain enhancer of activated B cell

NK

Natural killer

NPV

Negative predictive value

NR

Null responders

PEG-IFN

Pegylated-interferon

RAS gene

Rat sarcoma gene

RF

Rheumatoid factor

RSL

Reactive-site loop

SCCA1/Serpin B3

Serpin member gene 3

SCCA2/serpinB4

Serpin member gene 4

SCCA-IgM

Squamous cell carcinoma antigen-immunoglobulin M

sIgM

Secreted IgM

SLE

Systemic lupus erythematosus

SVR

Sustained virological response

TGF-β

Transforming growth factor-beta

TNF-α

Tumor necrosis factor-alpha

US

Ultrasound

References

  1. Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology. 2007;46:380–7.CrossRefPubMedGoogle Scholar
  2. Beneduce L, Castaldi F, Marino M, et al. Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma. Cancer. 2005;103:2558–65.CrossRefPubMedGoogle Scholar
  3. Beneduce L, Prayer-Galetti T, Giustinian AM, et al. Detection of prostate-specific antigen coupled to immunoglobulin M in prostate cancer patients. Cancer Detect Prev. 2007;31:402–7.CrossRefPubMedGoogle Scholar
  4. Bhardwaj N. Harnessing the immune system to treat cancer. J Clin Invest. 2007;117:1130–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Biasiolo A, Chemello L, Quarta S, et al. Monitoring SCCA-IgM complexes in serum predicts liver disease progression in patients with chronic hepatitis. J Viral Hepat. 2008;15:246–9.CrossRefPubMedGoogle Scholar
  6. Biasiolo A, Tono N, Ruvoletto M, et al. IgM-linked SerpinB3 and SerpinB4 in sera of patients with chronic liver disease. PLoS One. 2012;7:e40658.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Biasiolo A, Tono N, Zaninotto M, et al. Specificity of squamous cell carcinoma antigen (SCCA)-IgM detection in patients with HCV infection and rheumatoid factor seropositivity. J Med Virol. 2013;85:1005–8.CrossRefPubMedGoogle Scholar
  8. Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.CrossRefPubMedGoogle Scholar
  9. Bolondi L, Gramantieri L. From liver cirrhosis to HCC. Intern Emerg Med. 2011;6 Suppl 1:93–8.CrossRefPubMedGoogle Scholar
  10. Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.CrossRefPubMedGoogle Scholar
  11. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Buccione D, Fatti G, Gallotta A, et al. Serum SCCA-IgM as a predictor of hepatocellular carcinoma in patients with liver cirrhosis. Open J Gastroenterol. 2012;2:56–61.CrossRefGoogle Scholar
  13. Cabibbo G, Craxi A. Epidemiology, risk factors and surveillance of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2010;14:352–5.PubMedGoogle Scholar
  14. Calabrese F, Lunardi F, Giacometti C, et al. Overexpression of squamous cell carcinoma antigen in idiopathic pulmonary fibrosis: clinicopathological correlations. Thorax. 2008;63:795–802.CrossRefPubMedGoogle Scholar
  15. Cannito S, Novo E, Compagnone A, et al. Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. Carcinogenesis. 2008;29:2267–78.CrossRefPubMedGoogle Scholar
  16. Cannito S, Turato C, Paternostro C, et al. Hypoxia up-regulates SERPINB3 through HIF-2alpha in human liver cancer cells. Oncotarget. 2015;6:2206–21.CrossRefPubMedGoogle Scholar
  17. Castaldi F, Marino M, Beneduce L, et al. Detection of circulating CEA-IgM complexes in early stage colorectal cancer. Int J Biol Markers. 2005;20:204–8.PubMedGoogle Scholar
  18. Cataltepe S, Gornstein ER, Schick C, et al. Co-expression of the squamous cell carcinoma antigens 1 and 2 in normal adult human tissues and squamous cell carcinomas. J Histochem Cytochem. 2000;48:113–22.CrossRefPubMedGoogle Scholar
  19. Catanzaro JM, Sheshadri N, Pan JA, et al. Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. Nat Commun. 2014;5:3729.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Chechlinska M, Kowalewska M, Brzoska-Wojtowicz E, et al. Squamous cell carcinoma antigen 1 and 2 expression in cultured normal peripheral blood mononuclear cells and in vulvar squamous cell carcinoma. Tumour Biol. 2010;31:559–67.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ciscato F, Sciacovelli M, Villano G, et al. SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I. Oncotarget. 2014;5:2418–27.CrossRefPubMedGoogle Scholar
  22. Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.CrossRefPubMedGoogle Scholar
  23. Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10:778–86.CrossRefPubMedGoogle Scholar
  24. European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.CrossRefGoogle Scholar
  25. Fadini GP, Albiero M, Millioni R, et al. The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker. Diabetologia. 2014;57:1947–56.CrossRefPubMedGoogle Scholar
  26. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–72.CrossRefPubMedGoogle Scholar
  27. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.CrossRefPubMedGoogle Scholar
  28. Fransvea E, Trerotoli P, Sacco R, et al. SCCA-IC serum levels are predictive of clinical response in HCV chronic hepatitis to antiviral therapy: a multicentric prospective study. J Viral Hepat. 2012;19:704–10.CrossRefPubMedGoogle Scholar
  29. Giannelli G, Fransvea E, Trerotoli P, et al. Clinical validation of combined serological biomarkers for improved hepatocellular carcinoma diagnosis in 961 patients. Clin Chim Acta. 2007a;383:147–52.CrossRefPubMedGoogle Scholar
  30. Giannelli G, Iannone F, Fransvea E, et al. Squamous cellular carcinoma immunocomplexed is increased in scleroderma patients with lung fibrosis. Clin Exp Rheumatol. 2007b;25:794–5.PubMedGoogle Scholar
  31. Giannini EG, Basso M, Bazzica M, et al. Successful antiviral therapy determines a significant decrease in squamous cell carcinoma antigen-associated (SCCA) variants’ serum levels in anti-HCV positive cirrhotic patients. J Viral Hepat. 2010;17:563–8.CrossRefPubMedGoogle Scholar
  32. Guido M, Roskams T, Pontisso P, et al. Squamous cell carcinoma antigen in human liver carcinogenesis. J Clin Pathol. 2008;61:445–7.CrossRefPubMedGoogle Scholar
  33. Hensel F, Hermann R, Schubert C, et al. Characterization of glycosylphosphatidylinositol-linked molecule CD55/decay-accelerating factor as the receptor for antibody SC-1-induced apoptosis. Cancer Res. 1999;59:5299–306.PubMedGoogle Scholar
  34. Kato H. Expression and function of squamous cell carcinoma antigen. Anticancer Res. 1996;16:2149–53.PubMedGoogle Scholar
  35. Kato H, Torigoe T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer. 1977;40:1621–8.CrossRefPubMedGoogle Scholar
  36. Lee E, Edward S, Singal AG, et al. Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time. Clin Gastroenterol Hepatol. 2013;11:437–40.CrossRefPubMedGoogle Scholar
  37. Li C, Zhang Z, Zhang P, Liu J. Diagnostic accuracy of des-gamma-carboxy prothrombin versus alpha-fetoprotein for hepatocellular carcinoma: a systematic review. Hepatol Res. 2014;44:E11–25.CrossRefPubMedGoogle Scholar
  38. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138:493–502.CrossRefPubMedGoogle Scholar
  39. Lunardi F, Villano G, Perissinotto E, et al. Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice. Lab Invest. 2011;91:945–54.CrossRefPubMedGoogle Scholar
  40. Marcello A, Wirths O, Schneider-Axmann T, et al. Circulating immune complexes of Abeta and IgM in plasma of patients with Alzheimer’s disease. J Neural Transm. 2009;116:913–20.CrossRefPubMedCentralGoogle Scholar
  41. Martini A, Fattovich G, Guido M, et al. HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients. J Viral Hepat. 2015;22:800–8.CrossRefPubMedGoogle Scholar
  42. Masumoto K, Sakata Y, Arima K, et al. Inhibitory mechanism of a cross-class serpin, the squamous cell carcinoma antigen 1. J Biol Chem. 2003;278:45296–304.CrossRefPubMedGoogle Scholar
  43. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–93.CrossRefPubMedGoogle Scholar
  44. McMahon BJ, Bulkow L, Harpster A, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology. 2000;32:842–6.CrossRefPubMedGoogle Scholar
  45. Mossad NA, Mahmoud EH, Osman EA, et al. Evaluation of squamous cell carcinoma antigen-immunoglobulin M complex (SCCA-IGM) and alpha-l-fucosidase (AFU) as novel diagnostic biomarkers for hepatocellular carcinoma. Tumour Biol. 2014;35:11559–64.CrossRefPubMedGoogle Scholar
  46. Murakami A, Suminami Y, Hirakawa H, et al. Squamous cell carcinoma antigen suppresses radiation-induced cell death. Br J Cancer. 2001;84:851–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Nakamura S, Nouso K, Sakaguchi K, et al. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol. 2006;101:2038–43.CrossRefPubMedGoogle Scholar
  48. Pontisso P, Calabrese F, Benvegnu L, et al. Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma. Br J Cancer. 2004;90:833–7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pontisso P, Quarta S, Caberlotto C, et al. Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma. Int J Cancer. 2006;119:735–40.CrossRefPubMedGoogle Scholar
  50. Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.CrossRefPubMedGoogle Scholar
  51. Pozzan C, Cardin R, Piciocchi M, et al. Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC). J Gastroenterol Hepatol. 2014;29:1637–44.CrossRefPubMedGoogle Scholar
  52. Quarta S, Vidalino L, Turato C, et al. SERPINB3 induces epithelial-mesenchymal transition. J Pathol. 2010;221:343–56.CrossRefPubMedGoogle Scholar
  53. Sakata Y, Arima K, Takai T, et al. The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, Der p 1. J Biol Chem. 2004;279:5081–7.CrossRefGoogle Scholar
  54. Schick C, Kamachi Y, Bartuski AJ, et al. Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase. J Biol Chem. 1997;272:1849–55.CrossRefGoogle Scholar
  55. Schick C, Pemberton PA, Shi GP, et al. Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis. Biochemistry. 1998;37:5258–66.CrossRefPubMedGoogle Scholar
  56. Schütte K, Schulz C, Link A, et al. Current biomarkers for hepatocellular carcinoma: surveillance, diagnosis and prediction of prognosis. World J Hepatol. 2015;7:139–49.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Silverman GJ. Regulatory natural autoantibodies to apoptotic cells: pallbearers and protectors. Arthritis Rheum. 2011;63:597–602.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30:37–47.CrossRefPubMedGoogle Scholar
  59. Sterling RK, Wright EC, Morgan TR, et al. Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C. Am J Gastroenterol. 2012;107:64–74.CrossRefPubMedGoogle Scholar
  60. Suminami Y, Kishi F, Sekiguchi K, et al. Squamous cell carcinoma antigen is a new member of the serine protease inhibitors. Biochem Biophys Res Commun. 1991;181:51–8.CrossRefPubMedGoogle Scholar
  61. Suminami Y, Nagashima S, Vujanovic NL, et al. Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1. Br J Cancer. 2000;82:981–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117:1137–46.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Takeshima N, Suminami Y, Takeda O, et al. Expression of mRNA of SCC antigen in squamous cells. Tumour Biol. 1992;13:338–42.CrossRefPubMedGoogle Scholar
  64. Trerotoli P, Fransvea E, Angelotti U, et al. Tissue expression of Squamous Cellular Carcinoma Antigen (SCCA) is inversely correlated to tumor size in HCC. Mol Cancer. 2009;8:29.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Trevisani F, De Notariis S, Rapaccini G, et al. Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol. 2002;97:734–44.CrossRefPubMedGoogle Scholar
  66. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383:1749–61.CrossRefPubMedGoogle Scholar
  67. Turato C, Buendia MA, Fabre M, et al. Over-expression of SERPINB3 in hepatoblastoma: a possible insight into the genesis of this tumour? Eur J Cancer. 2012;48:1219–26.CrossRefPubMedGoogle Scholar
  68. Turato C, Vitale A, Fasolato S, et al. SERPINB3 is associated with TGF-beta1 and cytoplasmic beta-catenin expression in hepatocellular carcinomas with poor prognosis. Br J Cancer. 2014;110:2708–15.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Vidalino L, Doria A, Quarta S, et al. SerpinB3 expression on B-cell surface in autoimmune diseases and hepatitis C virus-related chronic liver infection. Exp Biol Med. 2012;237:793–802.CrossRefGoogle Scholar
  70. Villano G, Ruvoletto M, Ceolotto G, et al. SERPINB3 is associated with longer survival in transgenic mice. Sci Rep. 2013;3:3056.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Villano G, Turato C, Quarta S, et al. Hepatic progenitor cells express SerpinB3. BMC Cell Biol. 2014;15:5.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Vollmers HP, Brändlein S. Natural antibodies and cancer. J Autoimmun. 2007;29:295–302.CrossRefPubMedGoogle Scholar
  73. Wan HG, Xu H, Gu YM, et al. Comparison osteopontin vs AFP for the diagnosis of HCC: a meta-analysis. Clin Res Hepatol Gastroenterol. 2014;38:706–14.CrossRefPubMedGoogle Scholar
  74. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417–22.PubMedGoogle Scholar
  75. Zuin J, Veggiani G, Pengo P, et al. Experimental validation of specificity of the squamous cell carcinoma antigen-immunoglobulin M (SCCA-IgM) assay in patients with cirrhosis. Clin Chem Lab Med. 2010;48:217–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of PaduaPaduaItaly
  2. 2.Xeptagen SpAVEGA ParkVeniceItaly

Personalised recommendations