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Immunoglobulin G Fc N-glycan profiling in patients with gastric cancer by LC-ESI-MS: relation to tumor progression and survival

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Abstract

The IgG Fc glycans strongly influence the Fcγ receptor interactions and Fc-mediated effector mechanisms. Changes in the structure of IgG glycans are associated with various diseases, such as infections and autoimmunity. However, the possible role of Fc glycans in tumor immunity is not yet fully understood. The aim of this study was to profile the Fc N-glycans of IgG samples from patients with gastric cancer (n = 80) and controls (n = 51) using LC-ESI-MS method to correlate the findings with stage of cancer and patients survival. Analysis of 32 different IgG N-glycans revealed significant increase of agalactosylated (GnGnF, GnGn(bi)F), and decrease of galactosylated (AGn(bi), AGn(bi)F, AA(bi), AAF) and monosialylated IgG glycoforms (NaAF, NaA(bi)) in cancer patients. A statistically significant increase of Fc fucosylation was observed in tumor stage II and III whereas reverse changes were found for the presence of bisecting GlcNAc. Higher level of fully sialylated glycans and elevated expression of glycans with bisecting GlcNAc were associated with better survival rate. Our findings provide the first evidence that the changes in Fc glycan profile may predict the survival of patients with gastric cancer. Cancer stage-dependent changes in Fc fucosylation and the bisecting N-acteylglucosamine expression as well as an association of several IgG glycoforms with the survival suggest that IgG glycosylation is related to pathogenesis of cancer and progression of the disease.

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References

  1. Arnold, J.N., Wormald, M.R., Sim, R.B., Rudd, P.M., Dwek, R.A.: The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. (2007). doi:10.1146/annurev.immunol.25.022106.141702

  2. Nose, M., Wigzell, H.: Biological significance of carbohydrate chains on monoclonal antibodies. Proc. Natl. Acad. Sci. U.S.A. 80, 6632–6636 (1983)

    Article  PubMed  CAS  Google Scholar 

  3. Jefferis, R., Lund, J., Pound, J.D.: IgG-Fc mediated effector functions: molecular definition of interaction sites for effector ligands and the role of glycosylation. Immunol. Rev. 163, 59–76 (1998)

    Article  PubMed  CAS  Google Scholar 

  4. Margni, R., Malan Borel, I.: Paradoxical behaviour of asymmetric IgG antibodies. Immunol. Rev 163, 77–87 (1998)

    Article  PubMed  CAS  Google Scholar 

  5. Shields, R.L., Lai, J., Keck, R., O’Connell, L.Y., Hong, K., Meng, Y.G., Weikert, S.H., Presta, L.G.: Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J. Biol. Chem. (2002). doi:10.1074/jbc.M202069200

  6. Shinkawa, T., Nakamura, K., Yamane, N., Shoji-Hosaka, E., Kanda, Y., Sakurada, M., Uchida, K., Anazawa, H., Satoh, M., Yamasaki, M., Hanai, N., Shitara, K.: The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complextype oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. (2003). doi:10.1074/jbc.M210665200

  7. Barbin, K., Stieglmaier, J., Saul, D., Stieglmaier, K., Stockmeyer, B., Pfeiffer, M., Lang, P., Fey, G.H.: Influence of variable N-glycosylation on the cytolytic potential of chimeric CD19 antibodies. J. Immunother. (2006). doi:10.1097/01.cji.0000175684.28615.7b

  8. Raju, T.S.: Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. (2008). doi:10.1016/j.coi.2008.06.007

  9. Schroeder, H.W. Jr., Cavacini, L.: Structure and function of immunoglobulins. J. Allergy. Clin. Immunol. (2010). doi:10.1016/j.jaci.2009.09.046

  10. Wuhrer, M., Stam, J.C., van de Geijn, F.E., Koeleman, C.A., Verrips, C.T., Dolhain, R.J., Hokke, C.H., Deelder, A.M.: Glycosylation profiling of immunoglobulin G (IgG) subclasses from human serum. Proteomics (2007). doi:10.1002/pmic.200700289

  11. Holland, M., Takada, K., Okumoto, T., Takahashi, N., Kato, K., Adu, D., Bensmith, A., Harper, L., Savage, C.O.P., Jefferis, R.: Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis. Clin. Exp. Immunopl. 129(1), 183–190 (2002)

    Article  CAS  Google Scholar 

  12. Parekh, R.B., Dwek, R.A., Sutton, B.J., Fernandes, D.L., Leung, A., Stanworth, D., Rademacher, T.W., Mizuochi, T., Taniguchi, T., Matsuta, K., Takeuchi, F., Nagano, Y., Miyamoto, T., Kobata, A.: Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG. Nature 316, 452–457 (1985)

    Article  PubMed  CAS  Google Scholar 

  13. Parekh, R.B., Roitt, I.M., Isenberg, D.A., Dwek, R.A., Ansell, B.M., Rademacher, T.W.: Galactosylation of IgG associated oligosaccharides: Reduction in patients with adult and juvenile onset rheumatoid arthritis and relation to disease activity. Lancet 331, 966–969 (1988)

    Article  Google Scholar 

  14. Bond, A., Alavi, A., Axford, J.S., Bourke, B.E., Bruckner, F.E., Kerr, M.A., Maxwell, J.D., Tweed, K.J., Weldon, M.J., Youinou, P., Hay, F.C.: A detailed lectin analysis of IgG glycosylation, demonstrating disease specific changes in terminal galactose and N-acetylglucosamine. J. Autoimmun. (1997). doi:10.1006/jaut.1996.0104

  15. Dubé, R., Rook, G.A., Steele, J., Brealey, R., Dwek, R., Rademacher, T., Lennard-Jones, J.: Agalactosyl IgG in inflammatory bowel disease: correlation with creactive protein. Gut 31, 431–434 (1990)

    Article  PubMed  Google Scholar 

  16. Mehta, A.S., Long, R.E., Comunale, M.A., Wang, M., Rodemich, L., Krakover, J., Philip, R., Marrero, J.A., Dwek, R.A., Block, T.M.: Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. J. Virol. (2008). doi:10.1128/JVI.01600-07

  17. Moore, J.S., Wu, X., Kulhavy, R., Tomana, M., Novak, J., Moldoveanu, Z., Brown, R., Goepfert, P.A., Mestecky, J.: Increased levels of galactose-deficient IgG in sera of HIV-1-infected individuals. AIDS (2005). doi:10.1097/01.aids.0000161767.21405.68

  18. Stefanović, G., Marković, D., Ilić, V., Brajović, G., Petrović, S., Milosević-Jovcić, N.: Hypogalactosylation of salivary and gingival fluid immunoglobulin G in patients with advanced periodontitis. J. Periodontol (2006). doi:10.1902/jop.2006.060049

  19. Klaamas, K., Kodar, K., Kurtenkov, O.: An increased level of the Concanavalin A-positive IgG in the serum of patients with gastric cancer as evaluated by a lectin enzyme-linked immunosorbent assay (LELISA). Neoplasma 55(2), 143–50 (2008)

    PubMed  CAS  Google Scholar 

  20. Kodar, K., Kurtenkov, O., Klaamas, K.: The Thomsen-Friedenreich antigen and alphaGal-specific human IgG glycoforms: concanavalin A reactivity and relation to survival of cancer patients. Immunol. Invest. (2009). doi:10.3109/08820130903147193

  21. Wilm, M., Shevchenko, A., Houthaeve, T., Breit, S., Schweigerer, L., Fotsis, T., Mann, M.: Femtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry. Nature (1996). doi:10.1038/379466a0

  22. Bardor, M., Cabrera, G., Stadlmann, J., Lerouge, P., Cremata, J.A., Gomord, V., Fitchette, A.C.: N-glycosylation of plant recombinant pharmaceuticals. Methods Mol. Biol. (2009). doi:10.1007/978-1-59745-407-0_14

  23. Stadlmann, J., Pabst, M., Kolarich, D., Kunert, R., Altmann, F.: Analysis of immunoglobulin glycosylation by LC-ESI-MS of glycopeptides and oligosaccharides. Proteomics (2008). doi:10.1002/pmic.200700968

  24. Stadlmann, J., Weber, A., Pabst, M., Anderle, H., Kunert, R., Ehrlich, H.J., Peter, Schwarz. H,, Altmann, F.: A close look at human IgG sialylation and subclass distribution after lectin fractionation. Proteomics (2009). doi:10.1002/pmic.200800931

  25. Zhang, X., Asara, J.M., Adamec, J., Ouzzani, M., Elmagarmid, A.K.: Data preprocessing in liquid chromatography-mass spectrometry-based proteomics. Bioinformatics (2005). doi:10.1093/bioinformatics/bti660

  26. Altmann, F.: What’s your name, sugar? A simple abbreviation system for complex N-glycan structures. http://www.proglycan.com (2010). Accessed 28 June 2010.

  27. Kaneko, Y., Nimmerjahn, F., Ravetch, J.V.: Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science (2006). doi:10.1126/science.1129594

  28. Nimmerjahn, F., Anthony, R.M., Ravetch, J.V.: Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc. Natl. Acad. Sci. U. S. A. (2007). doi:10.1073/pnas.0702936104

  29. Nimmerjahn, F., Ravetch, J.V.: Analyzing antobody-Fc-receptor interactions. Methods Mol. Biol. (2008). doi:10.1007/978-1-59745-570-1_9

  30. Iida, S., Kuni-Kamochi, R., Mori, K., Misaka, H., Inoue, M., Okazaki, A., Shitara, K., Satoh, M.: Two mechanisms of the enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood. B.M.C. Cancer (2009). doi:10.1186/1471-2407-9-58

  31. Patel, D., Guo, X., Ng, S., Melchior, M., Balderes, P., Burtrum, D., Persaud, K., Luna, X., Ludwig, D.L., Kang, X.: IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab. Hum. Antibodies (2010). doi:10.3233/HAB-2010-0232

  32. Turner, G.A.: N-glycosylation of serum proteins in disease and its investigation using lectins. Clin. Chim. Acta. 266, 149–171 (1992)

    Article  Google Scholar 

  33. Hakomori, S.: Glycosylation defining cancer malignancy: new wine in an old bottle. P.N.A.S. (2002). doi:10.1073/pnas.172380699

  34. Brooks, S.A., Carter, T.M., Royle, L., Harvey, D.J., Fry, S.A., Kinch, C., Dwek, R.A., Rudd, P.M.: Altered glycosylation of proteins in cancer: what is the potential for new anti-tumour strategies. Anticancer Agents Med. Chem. 8(1), 2–21 (2008)

    Article  PubMed  CAS  Google Scholar 

  35. Arnold, J.N., Saldova, R., Galligan, M.C., Murphy, T.B., Mimura-Kimura, Y., Telford, J.E., Godwin, A.K., Rudd, P.M.: Novel glycan biomarkers for the detection of lung cancer. J. Proteome Res. (2011). doi:10.1021/pr101034t

  36. Gerçel-Taylor, C., Bazzett, L.B., Taylor, D.D.: Presence of aberrant tumor-reactive immunoglobulins in the circulation of patients with ovarian cancer. Gynecol. Oncol. (2001). doi:10.1006/gyno.2000.6102

  37. Bones, J., Byrne, J.C., O'Donoghue, N., McManus, C., Scaife, C., Boissin, H., Nastase, A., Rudd, P.M.: Glycomic and glycoproteomic analysis of serum from patients with stomach cancer reveals potential markers arising from host defense response mechanisms. J. Proteome Res. (2011). doi:10.1021/pr101036b

  38. Kanoh, Y., Mashiko, T., Danbara, M., Takayama, Y., Ohtani, S., Egawa, S., Baba, S., Akahoshi, T.: Changes in serum IgG oligosaccharide chains with prostate cancer progression. Anticancer Res 24(5B), 3135–9 (2004)

    PubMed  CAS  Google Scholar 

  39. Aurer, I., Lauc, G., Dumić, J., Rendić, D., Matisić, D., Milos, M., Heffer-Lauc, M., Flogel, M., Labar, B.: Aberrant glycosylation of Igg heavy chain in multiple myeloma. Coll. Antropol. 31(1), 247–51 (2007)

    PubMed  CAS  Google Scholar 

  40. Rademacher, T.W., Williams, P., Dwek, R.A.: Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc. Nat. Acad. Sci. U. S. A. 91, 6123–7 (1994)

    Article  CAS  Google Scholar 

  41. Selman, M.H., Niks, E.H., Titulaer, M.J., Verschuuren, J.J., Wuhrer, M., Deelder, A.M.: IgG Fc N glycosylation changes in Lambert-Eaton Myasthenic syndrome and Myasthenia Gravis. J. Proteome Res. (2011). doi:10.1021/pr1004373

  42. Huhn, C., Selman, M.H., Ruhaak, L.R., Deelder, A.M., Wuhrer, M.: IgG glycosylation analysis. Proteomics (2009). doi:10.1002/pmic.200800715

  43. Stadlmann, J., Pabst, M., Altmann, F.: Analytical and Functional Aspects of Antibody Sialylation. J. Clin. Immunol. (2010). doi:10.1007/s10875-010-9409-2

  44. Takahashi, M., Kuroki, Y., Ohtsubo, K., Taniguchi, N.: Core fucose and bisecting GlcNAc, the direct modifiers of the N-glycan core: their functions and target proteins. Carbohydr. Res. (2009). doi:10.1016/j.carres.2009.04.031

  45. Yamada, E., Tsukamoto, Y., Sasaki, R., Yagyu, K., Takahashi, N.: Structural changes of immunoglobulin G oligosaccharides with age in healthy human serum. Glycoconj. J. 14, 401–405 (1997)

    Article  PubMed  CAS  Google Scholar 

  46. Pucic, M., Knezevic, A., Vidic, J., Adamczyk, B., Novokmet, M., Polasek, O., Gornik, O., Supraha-Goreta, S., Wormald, M.R., Redzic, I., Campbell, H., Wright, A., Hastie, N.D., Wilson, J.F., Rudan, I., Wuhrer, M., Rudd, P.M., Josic, D., Lauc, G.: High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Mol. Cell Proteomics. 10, (2011). doi:10.1074/mcp.M111.010090

  47. Ruhaak, L.R., Uh, H.W., Beekman, M., Koeleman, C.A., Hokke, C.H., Westendorp, R.G., Wuhrer, M., Houwing-Duistermaat, J.J., Slagboom, P.E., Deelder, A.M.: Decreased levels of bisecting GlcNAc glycoforms of IgG are associated with human longevity. P.Lo.S. One (2010). doi:10.1371/journal.pone.0012566

  48. Kurtenkov, O., Miljukhina, L., Smorodin, J., Klaamas, K., Bovin, N., Ellamaa, M., Chuzmarov, V.: Natural IgM and IgG antibodies to Thomsen-Friedenreich (T) antigen in serum of patients with gastric cancer and blood donors–relation to Lewis (a, b) histo-blood group phenotype. Acta. Oncol. 38(7), 939–43 (1999)

    Article  PubMed  CAS  Google Scholar 

  49. Kurtenkov, O., Klaamas, K., Mensdorff-Pouilly, S., Miljukhina, L., Shljapnikova, L., Chuzmarov, V.: Humoral immune response to MUC1 and to the Thomsen-Friedenreich (TF) glycotope in patients with gastric cancer: relation to survival. Acta. Oncol. (2007). doi:10.1080/02841860601055441

  50. Raman, D., Baugher, P.J., Mon Thu, Y., Richmond, A.: Role of chemokines in tumor growth. Cancer Lett. (2007). doi:10.1016/j.canlet.2007.05.013

  51. Goldberg, J.E., Schwertfeder, K.L.: Proinflammatory cytokines in breast cancer: mechanism of action and potential targets for therapeutics. Curr. Drug Targets 11, 1133–46 (2010)

    Article  PubMed  CAS  Google Scholar 

  52. Kazatchkine, M.D., Kaveri, S.V.: Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N. Engl. J. Med. (2001). doi:10.1056/NEJMra993360

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Acknowledgments

We thank Prof. Dr. Friedrich Altmann for providing the MS instrument and for the opportunity to work in his laboratory (Glycobiology Division, University of Natural Resources and Applied Life Sciences). This work was supported by the Estonian Science Foundation (Grants #7317 and #8399) and by Archimedes Foundation scholarship.

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Authors and Affiliations

  1. National Institute for Health Development, Hiiu 42, Tallinn, 11619, Estonia

    Kristel Kodar, Kersti Klaamas, Boris Sergeyev & Oleg Kurtenkov

  2. Department of Chemistry, University of Natural Resources and Applied Life Sciences, Muthgasse 18, 1190, Vienna, Austria

    Johannes Stadlmann

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  1. Kristel Kodar
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  2. Johannes Stadlmann
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Correspondence to Kristel Kodar.

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Kodar, K., Stadlmann, J., Klaamas, K. et al. Immunoglobulin G Fc N-glycan profiling in patients with gastric cancer by LC-ESI-MS: relation to tumor progression and survival. Glycoconj J 29, 57–66 (2012). https://doi.org/10.1007/s10719-011-9364-z

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