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Investigation of nonspecific cross-reacting antigen 2 as a prognostic biomarker in bone marrow plasma from colorectal cancer patients

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Tumor Biology

An Erratum to this article was published on 06 May 2012

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Abstract

Carcinoembryonic antigen (CEA) is still the only routinely used biomarker in colorectal cancer (CRC), but its utility is hampered by poor specificity and sensitivity, and the search for novel biomarkers is highly warranted. The nonspecific cross-reacting antigen 2 (NCA-2), a truncated CEA species molecule which is transcribed from the same gene, has been suggested as an alternative biomarker to CEA. In the present work, specific immunofluorometric assays were used for detection of NCA-2 and full-length CEA in bone marrow plasma from 277 CRC patients to assess their value as prognostic biomarkers, and detection was also performed in tumor tissue and a CRC cell line. Elevated plasma CEA was associated with advanced tumor stage at diagnosis and adverse patient outcome, while for NCA-2, although the same trends were observed, no additional prognostic information was gained. While specific detection of NCA-2 was clearly achieved in plasma samples, cross-reactivity with full-length CEA was observed when the antigen was exposed to common fixation chemicals. The results from this study indicate that NCA-2 is probably not a prognostic biomarker in CRC and, furthermore, underline the issue of antibody specificity when investigating CEA species molecules.

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References

  1. Goldstein MJ, Mitchell EP. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest. 2005;23(4):338–51.

    Article  PubMed  Google Scholar 

  2. Hundt S, Haug U, Brenner H. Blood markers for early detection of colorectal cancer: a systematic review. Cancer Epidemiol Biomarkers Prev. 2007;16(10):1935–53. doi:10.1158/1055-9965.EPI-06-0994[doi].

    Article  PubMed  CAS  Google Scholar 

  3. Hanada H, Mugii S, Takeoka K, Maeda I, Watanabe M, Hidaka Y, et al. Early detection of colorectal cancer metastasis and relapse by recognizing nonspecific cross-reacting antigen 2 in commercial carcinoembryonic antigen assays. Clin Chem. 2009;55(9):1747–8.

    Article  PubMed  CAS  Google Scholar 

  4. Tan E, Gouvas N, Nicholls RJ, Ziprin P, Xynos E, Tekkis PP. Diagnostic precision of carcinoembryonic antigen in the detection of recurrence of colorectal cancer. Surg Oncol. 2009;18(1):15–24.

    Article  PubMed  Google Scholar 

  5. Takagawa R, Fujii S, Ohta M, Nagano Y, Kunisaki C, Yamagishi S, et al. Preoperative serum carcinoembryonic antigen level as a predictive factor of recurrence after curative resection of colorectal cancer. Ann Surg Oncol. 2008;15(12):3433–9.

    Article  PubMed  Google Scholar 

  6. Wang JY, Lu CY, Chu KS, Ma CJ, Wu DC, Tsai HL, et al. Prognostic significance of pre- and postoperative serum carcinoembryonic antigen levels in patients with colorectal cancer. Eur Surg Res. 2007;39(4):245–50.

    Article  PubMed  CAS  Google Scholar 

  7. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122(3):467–81.

    Article  PubMed  CAS  Google Scholar 

  8. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9(2):67–81.

    Article  PubMed  CAS  Google Scholar 

  9. Bhatnagar J, Tewari HB, Bhatnagar M, Austin GE. Comparison of carcinoembryonic antigen in tissue and serum with grade and stage of colon cancer. Anticancer Res. 1999;19(3B):2181–7.

    PubMed  CAS  Google Scholar 

  10. Rieger A, Wahren B. CEA levels at recurrence and metastases; importance for detecting secondary disease. Scand J Gastroenterol. 1975;10(8):869–74.

    PubMed  CAS  Google Scholar 

  11. Wanebo HJ, Rao B, Pinsky CM, Hoffman RG, Stearns M, Schwartz MK, et al. Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. N Engl J Med. 1978;299(9):448–51.

    Article  PubMed  CAS  Google Scholar 

  12. Herszenyi L, Farinati F, Cardin R, Istvan G, Molnar LD, Hritz I, et al. Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19–9 in colorectal cancer. BMC Cancer. 2008;8:194.

    Article  PubMed  Google Scholar 

  13. Nielsen HJ, Brunner N, Jorgensen LN, Olsen J, Rahr HB, Thygesen K, et al. Plasma TIMP-1 and CEA in detection of primary colorectal cancer: a prospective, population based study of 4509 high-risk individuals. Scand J Gastroenterol. 2011;46(1):60–9.

    Article  PubMed  CAS  Google Scholar 

  14. Wild N, Andres H, Rollinger W, Krause F, Dilba P, Tacke M, et al. A combination of serum markers for the early detection of colorectal cancer. Clin Cancer Res. 2010;16(24):6111–21.

    Article  PubMed  CAS  Google Scholar 

  15. Beauchemin N, Draber P, Dveksler G, Gold P, Gray-Owen S, Grunert F, et al. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp Cell Res. 1999;252(2):243–9.

    Article  PubMed  CAS  Google Scholar 

  16. Bormer OP. Major disagreements between immunoassays of carcinoembryonic antigen may be caused by nonspecific cross-reacting antigen 2 (NCA-2). Clin Chem. 1991;37(10 Pt 1):1736–9.

    PubMed  CAS  Google Scholar 

  17. Burtin P, Chavanel G, Hirsch-Marie H. Characterization of a second normal antigen that cross-reacts with CEA. J Immunol. 1973;111(6):1926–8.

    PubMed  CAS  Google Scholar 

  18. Burtin P, Sabine MC, Chavanel G. A comparative study of the localization of CEA and NCA2 in cancerous and normal gastrointestinal tissues. Int J Cancer. 1977;19(5):634–41.

    Article  PubMed  CAS  Google Scholar 

  19. Nagasaki H, Watanabe S, Kuroki M, Matsumoto Y, Murakami M, Omoda N, et al. An enzyme immunoassay for carcinoembryonic antigen (CEA) with homogeneous reactivity to different CEA preparations and low cross-reactivity with CEA-related normal antigens. J Immunol Methods. 1993;162(2):235–45.

    Article  PubMed  CAS  Google Scholar 

  20. Paus E, Almasbak H, Bormer OP, Warren DJ. A single-chain-Fv-based immunofluorometric assay specific for the CEA variant NCA-2. J Immunol Methods. 2003;283(1–2):125–39.

    Article  PubMed  CAS  Google Scholar 

  21. Flatmark K, Pedersen KB, Nesland JM, Rasmussen H, Aamodt G, Mikalsen SO, et al. Nuclear localization of the metastasis-related protein S100A4 correlates with tumour stage in colorectal cancer. J Pathol. 2003;200(5):589–95.

    Article  PubMed  CAS  Google Scholar 

  22. Folkvord S, Flatmark K, Dueland S, de Wijn R, Groholt KK, Hole KH, et al. Prediction of response to preoperative chemoradiotherapy in rectal cancer by multiplex kinase activity profiling. Int J Radiat Oncol Biol Phys. 2010;78(2):555–62.

    Article  PubMed  CAS  Google Scholar 

  23. Bormer OP, Nustad K. Selection of monoclonal antibodies for use in an immunometric assay for carcinoembryonic antigen. J Immunol Methods. 1990;127(2):171–8.

    Article  PubMed  CAS  Google Scholar 

  24. Bormer OP. Interference of complement with the binding of carcinoembryonic antigen to solid-phase monoclonal antibodies. J Immunol Methods. 1989;121(1):85–93.

    Article  PubMed  CAS  Google Scholar 

  25. Bjerner J, Lebedin Y, Bellanger L, Kuroki M, Shively JE, Varaas T, et al. Protein epitopes in carcinoembryonic antigen. Report of the ISOBM TD8 workshop. Tumour Biol. 2002;23(4):249–62.

    Article  PubMed  CAS  Google Scholar 

  26. Nazato DM, Matos LL, Waisberg DR, Souza JR, Martins LC, Waisberg J. Prognostic value of carcinoembryonic antigen distribution in tumor tissue of colorectal carcinoma. Arq Gastroenterol. 2009;46(1):26–31.

    Article  PubMed  Google Scholar 

  27. Louhimo J, Carpelan-Holmstrom M, Alfthan H, Stenman UH, Jarvinen HJ, Haglund C. Serum HCG beta, CA 72–4 and CEA are independent prognostic factors in colorectal cancer. Int J Cancer. 2002;101(6):545–8.

    Article  PubMed  Google Scholar 

  28. Wang WS, Lin JK, Chiou TJ, Liu JH, Fan FS, Yen CC, et al. Preoperative carcinoembryonic antigen level as an independent prognostic factor in colorectal cancer: Taiwan experience. Jpn J Clin Oncol. 2000;30(1):12–6.

    Article  PubMed  Google Scholar 

  29. Blake KE, Dalbow MH, Concannon JP, Hodgson SE, Brodmerkel Jr GJ, Panahandeh AH, et al. Clinical significance of the preoperative plasma carcinoembryonic antigen (CEA) level in patients with carcinoma of the large bowel. Dis Colon Rectum. 1982;25(1):24–32.

    Article  PubMed  CAS  Google Scholar 

  30. Lindmark G, Bergstrom R, Pahlman L, Glimelius B. The association of preoperative serum tumour markers with Dukes' stage and survival in colorectal cancer. Br J Cancer. 1995;71(5):1090–4.

    Article  PubMed  CAS  Google Scholar 

  31. Hedin A, Carlsson L, Berglund A, Hammarstrom S. A monoclonal antibody-enzyme immunoassay for serum carcinoembryonic antigen with increased specificity for carcinomas. Proc Natl Acad Sci U S A. 1983;80(11):3470–4.

    Article  PubMed  CAS  Google Scholar 

  32. Matsuoka Y. CEA and related antigens as possible new tumor markers. Gan To Kagaku Ryoho. 1983;10(8):1754–63.

    PubMed  CAS  Google Scholar 

  33. Li M, Li JY, Zhao AL, He JS, Zhou LX, Li YA, et al. Comparison of carcinoembryonic antigen prognostic value in serum and tumour tissue of patients with colorectal cancer. Colorectal Dis. 2009;11(3):276–81.

    Article  PubMed  CAS  Google Scholar 

  34. Kuroki M, Haruno M, Arakawa F, Wakisaka M, Matsuoka Y. Reaction profiles of seven enzyme immunoassay kits for carcinoembryonic antigen (CEA) analyzed with purified preparations of CEA and related normal antigens. Clin Biochem. 1992;25(1):29–35.

    Article  PubMed  CAS  Google Scholar 

  35. Kuroki M, Yamaguchi A, Koga Y, Matsuoka Y. Antigenic reactivities of purified preparations of carcinoembryonic antigen (CEA) and related normal antigens using four different radioimmunoassay systems for CEA. J Immunol Methods. 1983;60(1–2):221–33.

    Article  PubMed  CAS  Google Scholar 

  36. van Essen HF, Verdaasdonk MA, Elshof SM, de Weger RA, van Diest PJ. Alcohol based tissue fixation as an alternative for formaldehyde: influence on immunohistochemistry. J Clin Pathol. 2010;63(12):1090–4.

    Article  PubMed  Google Scholar 

  37. Jones ML. How formalin affects the outcome of routine and special stains. Biotech Histochem. 2007;82(3):155–9.

    Article  PubMed  CAS  Google Scholar 

  38. Koga Y, Kuroki M, Matsunaga A, Shinoda T, Takayasu T, Matsuoka Y. Further comparative studies on chemical properties of carcinoembryonic antigen in tumor tissues and closely related antigens in adult feces and meconium. Mol Immunol. 1985;22(1):67–73.

    Article  PubMed  CAS  Google Scholar 

  39. Dapson RW. Macromolecular changes caused by formalin fixation and antigen retrieval. Biotech Histochem. 2007;82(3):133–40.

    Article  PubMed  CAS  Google Scholar 

  40. Noguchi M, Furuya S, Takeuchi T, Hirohashi S. Modified formalin and methanol fixation methods for molecular biological and morphological analyses. Pathol Int. 1997;47(10):685–91.

    Article  PubMed  CAS  Google Scholar 

  41. Paulson JC. Glycoproteins: what are the sugar chains for? Trends in Biochemical Sciences. 1989;14(7):272–6.

    Article  PubMed  CAS  Google Scholar 

  42. Yamashita K, Totani K, Iwaki Y, Kuroki M, Matsuoka Y, Endo T, et al. Carbohydrate structures of nonspecific cross-reacting antigen-2, a glycoprotein purified from meconium as an antigen cross-reacting with anticarcinoembryonic antigen antibody. Occurrence of complex-type sugar chains with the Gal beta 1—3GlcNAc beta 1—3Gal beta 1—4GlcNAc beta 1—outer chains. J Biol Chem. 1989;264(30):17873–81.

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Ellen Hellesylt, Anne Marie Sauren, and Miriam Øijordsbakken for excellent technical assistance and Ole Børmer and Mads Haugland Haugen for valuable discussions. This work was supported by South-Eastern Norway Regional Health Authority and Norwegian Foundation for Health and Rehabilitation.

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Correspondence to Kristina Schee.

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Schee, K., Flatmark, K., Holm, R. et al. Investigation of nonspecific cross-reacting antigen 2 as a prognostic biomarker in bone marrow plasma from colorectal cancer patients. Tumor Biol. 33, 73–83 (2012). https://doi.org/10.1007/s13277-011-0247-5

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  • DOI: https://doi.org/10.1007/s13277-011-0247-5

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