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  • Review Article
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Glycans in cancer and inflammation — potential for therapeutics and diagnostics

Key Points

  • Glycans, which decorate all eukaryotic cell surfaces, undergo changes in structure with the onset of diseases such as cancer and inflammation. This article highlights some examples of disease-associated glycans and the possibility of exploiting these glycans for therapeutic or diagnostic strategies.

  • Cancer-associated changes in glycosylation include both the under- and overexpression of naturally-occurring glycans as well as neoexpression of glycans normally restricted to embryonic tissues. These structures most often arise from changes in the expression levels of glycosylating enzymes (glycosyltransferases and glycosidases) in cancerous versus healthy cells.

  • To dissect the roles of glycans in metastasis and tumour formation, cellular glycans have been structurally perturbed in a number of ways. The general conclusion of these studies is that certain glycans seem to play a role in cancer progression.

  • Given the functional link between aberrant glycosylation and malignancy, therapeutics that block the formation of cancer-associated glycans might have an effect on tumour progression. The immune system can be recruited to target cancer cells on the basis of their altered glycosylation.

  • Several glycan-based vaccines are presently undergoing clinical evaluation with some encouraging preliminary results.

  • Existing diagnostic methods used to monitor tumour-specific glycosylation require surgical biopsy followed by histological analysis with lectins or monoclonal antibodies. An interesting future direction in the field is to target aberrant glycosylation with probes for non-invasive imaging.

  • Specific carbohydrate epitopes, such as 6-sulpho sialyl Lewis x, initiate leukocyte homing to sites of chronic inflammation by enabling leukocyte-endothelial cell adhesion via the leukocyte receptor L-selectin and are specifically expressed at disease sites.

  • Drugs that block the selectins or the biosynthesis of their glycan ligands are under investigation in the pharmaceutical industry. In addition, there is an opportunity for the development of noninvasive diagnostics that might identify sites of chronic inflammation prior to the presentation of disease symptoms.

Abstract

Changes in glycosylation are often a hallmark of disease states. For example, cancer cells frequently display glycans at different levels or with fundamentally different structures than those observed on normal cells. This phenomenon was first described in the early 1970s, but the molecular details underlying such transformations were poorly understood. In the past decade advances in genomics, proteomics and mass spectrometry have enabled the association of specific glycan structures with disease states. In some cases, the functional significance of disease-associated changes in glycosylation has been revealed. This review highlights changes in glycosylation associated with cancer and chronic inflammation and new therapeutic and diagnostic strategies that are based on the underlying glycobiology.

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Figure 1: Cancer-associated glycans.
Figure 2: Carbohydrate-based anticancer vaccines.
Figure 3: Disaccharide decoys act as metabolic inhibitors of glycosylation.
Figure 4: Imaging chemically modified cellular glycans in vivo.

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References

  1. Fabbro, D. & Garcia-Echeverria, C. Targeting protein kinases in cancer therapy. Curr. Opin. Drug Disc. Dev. 5, 701–712 (2002).

    CAS  Google Scholar 

  2. Sliva, D. Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr. Cancer Drug Targ. 4, 327–336 (2004).

    Article  CAS  Google Scholar 

  3. Palladino, M. A., Bahjat, F. R., Theodorakis, E. A. & Moldawer, L. L. Anti-TNF-alpha therapies: The next generation. Nat. Rev. Drug Disc. 2, 736–746 (2003).

    Article  CAS  Google Scholar 

  4. Meezan, E., Wu, H. C., Black, P. H. & Robbins, P. W. Comparative studies on carbohydrate-containing membrane components of normal and virus-transformed mouse fibroblasts. Separation of glycoproteins and glycopeptides by sephadex chromatography. Biochemistry 8, 2518–2524 (1969). The first demonstration that cancer glycans differ from glycans on healthy cells.

    Article  CAS  PubMed  Google Scholar 

  5. Turner, G. A. N-Glycosylation of serum-proteins in disease and its investigation using lectins. Clin. Chim. Acta 208, 149–171 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Axford, J. S. Glycosylation and rheumatic disease. Biochim. Biophys. Acta 1455, 219–229 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Mackiewicz, A. & Mackiewicz, K. Glycoforms of serum α1-acid glycoprotein as markers of inflammation and cancer. Glycoconj. J. 12, 241–247 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Gabius, H. J. Biological information transfer beyond the genetic code: the sugar code. Natur Wissenschaften 87, 108–121 (2000).

    Article  CAS  Google Scholar 

  9. Saussez, S. et al. Quantitative glycohistochemistry defines new prognostic markers for cancers of the oral cavity. Cancer 82, 252–260 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Shriver, Z., Raguram, S. & Sasisekharan, R. Glycomics: a pathway to a class of new and improved therapeutics. Nat. Rev. Drug Disc. 3, 863–873 (2004).

    Article  CAS  Google Scholar 

  11. Pancino, G. et al. Purification and characterization of a breast-cancer-associated glycoprotein not expressed in normal breast and identified by monoclonal antibody-83d4. Brit. J. Cancer 63, 390–398 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Matsushita, Y., Cleary, K. R., Ota, D. M., Hoff, S. D. & Irimura, T. Sialyl-dimeric Lewis-X antigen expressed on mucin-like glycoproteins in colorectal-cancer metastases. Lab. Invest. 63, 780–791 (1990).

    CAS  PubMed  Google Scholar 

  13. Dennis, J. W., Laferte, S., Waghorne, C., Breitman, M. L. & Kerbel, R. S. β1-6 branching of asn-linked oligosaccharides is directly associated with metastasis. Science 236, 582–585 (1987).

    Article  CAS  PubMed  Google Scholar 

  14. Kim, Y. J. & Varki, A. Perspectives on the significance of altered glycosylation of glycoproteins in cancer. Glycoconj. J. 14, 569–576 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Sell, S. Cancer-associated carbohydrates identified by monoclonal antibodies. Human Path. 21, 1003–1019 (1990).

    Article  CAS  Google Scholar 

  16. Hakomori, S. & Zhang, Y. Glycosphingolipid antigens and cancer therapy. Chem. Biol. 4, 97–104 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Taylorpapadimitriou, J. & Epenetos, A. A. Exploiting altered glycosylation patterns in cancer- progress and challenges in diagnosis and therapy. Trends Biotech. 12, 227–233 (1994).

    Article  CAS  Google Scholar 

  18. Gabius, H. J. Tumor lectinology- at the intersection of carbohydrate chemistry, biochemistry, cell biology, and oncology. Angew. Chem. 27, 1267–1276 (1988).

    Article  Google Scholar 

  19. Orntoft, T. F. & Vestergaard, E. M. Clinical aspects of altered glycosylation of glycoproteins in cancer. Electrophoresis 20, 362–371 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Hollingsworth, M. A. & Swanson, B. J. Mucins in cancer: Protection and control of the cell surface. Nat. Rev. Cancer 4, 45–60 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Hakomori, S. Traveling for the glycosphingolipid path. Glycoconj. J. 17, 627–647 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, S. L. et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry. 1. Focus on gangliosides. Int. J. Cancer 73, 42–49 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, S. L. et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry. 2. Blood group–related antigens. Int. J. Cancer 73, 50–56 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Fukuda, M. Possible roles of tumor-associated carbohydrate antigens. Cancer Res. 56, 2237–44 (1996).

    CAS  PubMed  Google Scholar 

  25. Jurianz, K. et al. Complement resistance of tumor cells: Basal and induced mechanisms. Mol. Immunol. 36, 929–939 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Speiser, D. E. et al. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: Implications for immunotherapy. J. Exp. Med. 186, 645–653 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Danishefsky, S. J. & Allen, J. R. From the laboratory to the clinic: A retrospective on fully synthetic carbohydrate-based anticancer vaccines. Angew. Chem. 39, 836–863 (2000). An excellent review of synthetic carbohydrate-based anticancer vaccines.

    Article  CAS  Google Scholar 

  28. Livingston, P. O. Approaches to augmenting the immunogenicity of melanoma gangliosides- from whole melanoma-cells to ganglioside-KLH conjugate vaccines. Immunol. Rev. 145, 147–166 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Ragupathi, G. et al. On the power of chemical synthesis: Immunological evaluation of models for multiantigenic carbohydrate-based cancer vaccines. Proc. Nat'l Acad. Sci. U. S. A. 99, 13699–13704 (2002).

    Article  CAS  Google Scholar 

  30. Gilewski, T. et al. Immunization of metastatic breast cancer patients with a fully synthetic globe H conjugate: A phase I trial. Proc. Nat'l Acad. Sci. U. S. A. 98, 3270–3275 (2001).

    Article  CAS  Google Scholar 

  31. Slovin, S. F. et al. Carbohydrate vaccines in cancer: Immunogenicity of a fully synthetic globo H hexasaccharide conjugate in man. Proc. Nat'l Acad. Sci. U. S. A. 96, 5710–5715 (1999).

    Article  CAS  Google Scholar 

  32. Chapman, P. B. et al. A phase II trial comparing five dose levels of BEC2 anti-idiotypic monoclonal antibody vaccine that mimics GD3 ganglioside. Vaccine 22, 2904–2909 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Krug, L. M. et al. Vaccination of small cell lung cancer patients with polysialic acid or N-propionylated polysialic acid conjugated to keyhole limpet hemocyanin. Clin. Cancer Res. 10, 916–923 (2004). The first demonstration in humans that vaccines containing unnatural sugars mount a more robust immune response against cancer glycans than their natural counterparts.

    Article  CAS  PubMed  Google Scholar 

  34. Ragupathi, G. et al. Consistent antibody response against ganglioside GD2 induced in patients with melanoma by a GD2 lactone-keyhole limpet hemocyanin conjugate vaccine plus immunological adjuvant QS-21. Clin. Cancer Res. 9, 5214–5220 (2003).

    CAS  PubMed  Google Scholar 

  35. Dove, A. The bittersweet promise of glycobiology. Nat. Biotech. 19, 913–917 (2001).

    Article  CAS  Google Scholar 

  36. Holmberg, L. & Sandmaier, B. Vaccination with Theratope (STn-KLH) as treatment for breast cancer. Expert Rev. Vaccines 3, 655–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Livingston, P. O. The unfulfilled promise of melanoma vaccines. Clin. Cancer Res. 7, 1837–1838 (2001).

    CAS  PubMed  Google Scholar 

  38. Slovin, S. F. et al. Fully synthetic carbohydrate-based vaccines in biochemically relapsed prostate cancer: Clinical trial results with α-N-acetylgalactosamine-O-serine/threonine conjugate vaccine. J. Clin. Oncol. 21, 4292–4298 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Liu, T. M., Guo, Z. W., Yang, Q. L., Sad, S. & Jennings, H. J. Biochemical engineering of surface α2,8 polysialic acid for immunotargeting tumor cells. J. Biol. Chem. 275, 32832–32836 (2000). The first report on the use of unnatural sialic acid biosynthesis for tumour immunotherapy in animals.

    Article  CAS  PubMed  Google Scholar 

  40. Chefalo, P., Pan, Y. B., Nagy, N., Harding, C. & Guo, Z. W. Preparation and immunological studies of protein conjugates of N-acylneuraminic acids. Glycoconj. J. 20, 407–414 (2003).

    Article  Google Scholar 

  41. Pan, Y. B., Chefalo, P., Nagy, N., Harding, C. & Guo, Z. W. Synthesis and immunological properties of N-modified GM3 antigens as therapeutic cancer vaccines. J. Med. Chem. 48, 875–883 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zou, W. et al. Bioengineering of surface GD3 ganglioside for immunotargeting human melanoma cells. J. Biol. Chem. 279, 25390–25399 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Lemieux, G. A. & Bertozzi, C. R. Modulating cell surface immunoreactivity by metabolic induction of unnatural carbohydrate antigens. Chem. Biol. 8, 265–275 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Galili, U. Autologous tumor vaccines processed to express α-gal epitopes: a practical approach to immunotherapy in cancer. Cancer Immunol. Immunother. 53, 935–945 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Galili, U., Chen, Z. C. & DeGeest, K. Expression of α-gal epitopes on ovarian carcinoma membranes to be used as a novel autologous tumor vaccine. Gynecol. Oncol. 90, 100–108 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Deriy, L., Chen, Z. C., Gao, G. P. & Galili, U. Expression of α-gal epitopes on HeLa cells transduced with adenovirus containing α1,3galactosyltransferase cDNA. Glycobiology 12, 135–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Deriy, L., Ogawa, H., Gao, G. P. & Galili, U. In vivo targeting of vaccinating tumor cells to antigen—presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene. Cancer Gene Ther. (in press).

  48. Burchell, J. M., Mungul, A. & Taylor-Papadimitriou, J. O-linked glycosylation in the mammary gland: Changes that occur during malignancy. J. Mamm. Gland Biol. Neopl. 6, 355–364 (2001).

    Article  CAS  Google Scholar 

  49. Wong, N. K. et al. Characterization of the oligosaccharides associated with the human ovarian tumor marker CA125. J. Biol. Chem. 278, 28619–28634 (2003).

    Article  CAS  Google Scholar 

  50. Basu, P. S., Majhi, R. & Batabyal, S. K. Lectin and serum-PSA interaction as a screeninng test for prostate cancer. Clin. Biochem. 36, 373–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Peracaula, R. et al. Altered glycosylation pattern allows the distinction between prostate-specifc antigen (PSA) from normal and tumor origins. Glycobiology 13, 457–470 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. MacDonald, J. S. Carcinoembryonic antigen screening: Pros and cons. Sem. Oncol. 26, 556–560 (1999).

    CAS  Google Scholar 

  53. Lloyd, K. O., Burchell, J., Kudryashov, V., Yin, B. W. & Taylor-Papadimitriou, J. Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. Demonstration of simpler and fewer glycan chains in tumor cells. J. Biol. Chem. 271, 33325–34 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Dalziel, M. et al. The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J. Biol. Chem. 276, 11007–11015 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Ramanathan, R. K. et al. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advance pancreatic cancer. Cancer Immunol. Immunother. 54, 254–264 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Karanikas, V. et al. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. J. Clin. Invest. 100, 2783–2792 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xing, P. X. et al. Phase I study of synthetic MUC1 peptides in cancer. Int. J. Oncol. 6, 1283–1289 (1995).

    CAS  PubMed  Google Scholar 

  58. Renkonen, J., Paavonen, T. & Renkonen, R. Endothelial and epithelial expression of sialyl Lewis(x) and sialyl Lewis(a) in lesions of breast carcinoma. Int. J. Cancer 74, 296–300 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Miyake, M., Taki, T., Hitomi, S. & Hakomori, S. Correlation of expression of H/Le(Y)/Le(B) antigens with survival in patients with carcinoma of the lung. New Eng. J. Med. 327, 14–18 (1992).

    Article  CAS  PubMed  Google Scholar 

  60. Nakamori, S. et al. Increased expression of sialyl Lewis(X) antigen correlates with poor survival in patients with colorectal-carcinoma- clinicopathological and immunohistochemical study. Cancer Res. 53, 3632–3637 (1993).

    CAS  PubMed  Google Scholar 

  61. Shimodaira, K. et al. Carcinoma-associated expression of core 2 β1,6-N-acetylglucosaminyltransferase gene in human colorectal cancer: Role of O-glycans in tumor progression. Cancer Res. 57, 5201–5206 (1997).

    CAS  PubMed  Google Scholar 

  62. Gorelik, E., Galili, U. & Raz, A. On the role of cell surface carbohydrates and their binding proteins (lectins) in tumor metastasis. Cancer Metast. Rev. 20, 245–277 (2001).

    Article  CAS  Google Scholar 

  63. Guo, H. B., Lee, I., Kamar, M. & Pierce, M. N-Acetylglucosaminyltransferase V expression levels regulate cadherin-associated homotypic cell-cell adhesion and intracellular signaling pathways. J. Biol. Chem. 278, 52412–52424 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Demetriou, M., Nabi, I. R., Coppolino, M., Dedhar, S. & Dennis, J. W. Reduced contact-inhibition and substratum adhesion in epithelial-cells expressing GlcNAc-transferase-V. J. Cell Biol. 130, 383–392 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Stanley, P. Selection of lectin-resistant mutants of animal-cells. Meth. Enz. 96, 157–184 (1983).

    Article  CAS  Google Scholar 

  66. Tao, T. W. & Burger, M. M. Non-metastasizing variants selected from metastasizing melanoma cells. Nature 270, 437–438 (1977).

    Article  CAS  PubMed  Google Scholar 

  67. Tokuyama, S. et al. Suppression of pulmonary metastasis in murine B16 melanoma cells by transfection of a sialidase cDNA. Int. J. Cancer 73, 410–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Granovsky, M. et al. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nature Med. 6, 306–312 (2000). This paper describes reduced mammary tumour growth and metastasis in Mgat5−/− mice than in transgenic littermates expressing Mgat5, supporting the role of the branching β1,6GlcNAc residue in cancer progression.

    Article  CAS  PubMed  Google Scholar 

  69. Tang, D. G. & Honn, K. V. Adhesion molecules and tumor-metastasis- an update. Inv. Metast. 14, 109–122 (1994).

    CAS  Google Scholar 

  70. McEver, R. P. Selectin-carbohydrate interactions during inflammation and metastasis. Glycoconj. J. 14, 585–591 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Foster, M. M., Brown, J. R., Wang, L. C. & Esko, J. D. A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Res. 63, 2775–2781 (2003). A description of a small molecule glycosylation inhibitor capable of decreasing metastasis in a murine tumour model.

    Google Scholar 

  72. Sarkar, A. K., Rostand, K. S., Jain, R. K., Matta, K. L. & Esko, J. D. Fucosylation of disaccharide precursors of sialyl Lewis(X) inhibit selectin-mediated cell adhesion. J. Biol. Chem. 272, 25608–25616 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Brown, J. R., Fuster, M. M., Whisenant, T. & Esko, J. D. Expression patterns of α 2,3-sialyltransferases and α1,3-fucosyltransferases determine the mode of sialyl Lewis X inhibition by disaccharide decoys. J. Biol. Chem. 278, 23352–23359 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Alper, J. Glycobiology- Turning sweet on cancer. Science 301, 159–160 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Borsig, L. et al. Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Nat'l Acad. Sci. U. S. A. 98, 3352–3357 (2001).

    Article  CAS  Google Scholar 

  76. Borsig, L., Kim, Y. J., Varki, N. & Varki, A. The role of P-selectin and carcinoma mucins in tumor growth and metastasis. Glycobiology 8, 1143–1143 (1998). This report showed that heparin inhibits metastasis by interrupting glycan-mediated platelet tumour cell adhesion.

    Article  Google Scholar 

  77. Kim, Y. J., Borsig, L., Varki, N. M. & Varki, A. P-selectin deficiency attenuates tumor growth and metastasis. Proc. Nat'l Acad. Sci. U. S. A. 95, 9325–9330 (1998). The authors demonstrate that P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells than P selectin-expressing littermates.

    Article  CAS  Google Scholar 

  78. Shirota, K., Kato, Y., Irimura, T., Konda, H. & Sugiyama, Y. Anti-metastatic effect of the sialyl lewis-X analog GSC-150 on the human colon carcinoma derived cell line KM12-HX in the mouse. Biol. Pharm. Bull. 24, 316–319 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Zacharski, L. R. & Ornstein, D. L. Heparin and cancer. Thromb. Haemost. 80, 10–23 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Nitti, D. et al. Final results of a phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer. European Journal of Cancer 33, 1209–1215 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Weissleder, R. Scaling down imaging: molecular mapping of cancer in mice. Nat. Rev. Cancer 2, 11–8 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nat. Med. 9, 123–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Gambhir, S. S. Molecular imaging of cancer with positron emission tomography. Nat. Rev. Cancer 2, 683–93 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Sivolapenko, G. et al. Breast cancer imaging with radiolabelled peptide from complementary–determining region of antitumor immunity. Lancet 346 (1995).

  85. Moore, A., Medarova, Z., Potthast, A. & Dai, G. P. In vivo targeting of underglycosylated MUC-1 tumor antigen using a multimodal imaging probe. Cancer Research 64, 1821–1827 (2004). This report describes noninvasive imaging of breast cancer in a murine tumour model using a peptide that recognizes uMUC1.

    Article  CAS  PubMed  Google Scholar 

  86. Kayser, H. et al. Biosynthesis of a nonphysiological sialic-acid in different rat organs, using N-propanoyl-D-hexosamines as precursors. J. Biol. Chem. 267, 16934–16938 (1992).

    CAS  PubMed  Google Scholar 

  87. Prescher, J. P., Dube, D. H. & Bertozzi, C. R. Chemical remodeling of cell surfaces in living animals. Nature 430, 873–877 (2004). The first demonstration that the Staudinger ligation can tag azide-containing glycans in vivo.

    Article  CAS  PubMed  Google Scholar 

  88. Dube, D. H. & Bertozzi, C. R. Metabolic oligosaccharide engineering as a tool for glycobiology. Curr. Opin. Chem. Biol. 7, 616–625 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Keppler, O. T., Horstkorte, R., Pawlita, M., Schmidts, C. & Reutter, W. Biochemical engineering of the N-acyl side chain of sialic acid: biological implications. Glycobiology 11, 11R–18R (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Saxon, E. & Bertozzi, C. R. Cell surface engineering by a modified Staudinger reaction. Science 287, 2007–2010 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Lemieux, G. A., Yarema, K. J., Jacobs, C. L. & Bertozzi, C. R. Exploiting differences in sialoside expression for selective targeting of MRI contrast reagents. J. Am. Chem. Soc. 121, 4278–4279 (1999).

    Article  CAS  Google Scholar 

  92. Vocadlo, D. J., Hang, H. C., Kim, E. J., Hanover, J. A. & Bertozzi, C. R. A chemical approach for identifying O-GlcNAc-modified proteins in cells. Proc. Nat'l Acad. Sci. U. S. A. 100, 9116–9121 (2003).

    Article  CAS  Google Scholar 

  93. Hang, H. C., Yu, C., Kato, D. L. & Bertozzi, C. R. A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation. Proc. Nat'l Acad. Sci. U. S. A. 100, 14846–14851 (2003).

    Article  CAS  Google Scholar 

  94. Kansas, G. S. Selectins and their ligands: Current concepts and controversies. Blood 88, 3259–3287 (1996).

    CAS  PubMed  Google Scholar 

  95. Renkonen, J., Tynninen, O., Hayry, P., Paavonen, T. & Renkonen, R. Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites. Am. J. Pathol. 161, 543–550 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lowe, J. B. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr. Opin. Cell Biol. 15, 531–538 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Ley, K. The role of selectins in inflammation and disease. Trends Mol. Med. 9, 263–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Crocker, P. R. & Feizi, T. Carbohydrate recognition systems: Functional triads in cell-cell interactions. Curr. Opin. Struct. Biol. 6, 679–691 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Varki, A. Selectin ligands. Proc. Nat'l Acad. Sci. U. S. A. 91, 7390–7397 (1994).

    Article  CAS  Google Scholar 

  100. Michie, S. A., Streeter, P. R., Bolt, P. A., Butcher, E. C. & Picker, L. J. The human peripheral lymph-node vascular addressin- an inducible endothelial antigen involved in lymphocyte homing. Am. J. Pathol. 143, 1688–1698 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rosen, S. D. Endothelial ligands for L-selectin: From lymphocyte recirculation to allograft rejection. Am. J. Pathol. 155, 1013–1020 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kannagi, R. Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr. Opin. Struct. Biol. 12, 599–608 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Zollner, T. M. & Asadullah, K. Selectin and selectin ligand binding: a bittersweet attraction. J. Clin. Invest. 112, 980–983 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Khor, S. P., McCarthy, K., Dupont, M., Murray, K. & Timony, G. Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for phase I trial. J. Pharm. Exper. Ther. 293, 618–624 (2000).

    CAS  Google Scholar 

  105. Lee, L. V. et al. A potent and highly selective inhibitor of human α1,3-fucosyltransferase via click chemistry. J. Am. Chem. Soc. 125, 9588–9589 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Lin, C. H. et al. Enzymatic synthesis of a sialyl Lewis X dimer from egg yolk as an inhibitor of E-selectin. Bioorg. Med. Chem. 3, 1625–1630 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Dimitroff, C. J., Kupper, T. S. & Sackstein, R. Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen. J. Clin. Invest. 112, 1008–1018 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Armstrong, J. I. et al. A library approach to the generation of bisubstrate analoge sulfotransferse inhibitors. Org. Lett. 23, 2657–2660 (2001).

    Article  CAS  Google Scholar 

  109. Denis, M. C., Mahmood, U., Benoist, C., Mathis, D. & Weissleder, R. Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc. Nat'l Acad. Sci. U. S. A. 101, 12634–12639 (2004).

    Article  CAS  Google Scholar 

  110. Sibson, N. R. et al. MRI detection of early endothelial activation in brain inflammation. Mag. Reson. Med. 51, 248–252 (2004).

    Article  CAS  Google Scholar 

  111. Schofield, L., Hewitt, M. C., Evans, K., Siomos, M. A. & Seeberger, P. H. Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 418, 785–789 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Verez-Bencomo, V. et al. A synthetic conjugate polysaccharide vaccine against Haemophilus influenzae type b. Science 305, 522–525 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Mandal, M., Dudkin, V. Y., Geng, X. D. & Danishefsky, S. In pursuit of carbohydrate-based HIV vaccines, Part 1: The total synthesis of hybrid-type gp120 fragments. Angew. Chem. 43, 2557–2561 (2004).

    Article  CAS  Google Scholar 

  114. Geng, X. D., Dudkin, V. Y., Mandal, M. & Danishefsky, S. J. In pursuit of carbohydrate-based HIV vaccines, Part 2: The total synthesis of high-mannose-type gp120 fragments-evaluation of strategies directed to maximal convergence. Angew. Chem. 43, 2562–2565 (2004).

    Article  CAS  Google Scholar 

  115. Borman, S. Carbohydrate vaccines: novel chemical and enzymatic oligosaccharide synthesis techniques could lead to a new generation of carbohydrate–based vaccine agents. Chem. Eng. News 82, 31–35 (2004).

    Article  Google Scholar 

  116. Knutson, K. L. GMK (Progenics Pharmaceuticals). Curr. Opin. Invest. Drugs 3, 159–164 (2002).

    CAS  Google Scholar 

  117. Ragupathi, G. et al. A fully synthetic globo H carbohydrate vaccine induces a focused humoral response in prostate cancer patients: A proof of principle. Angew. Chem. 38, 563–566 (1999).

    Article  CAS  Google Scholar 

  118. Krug, L. M. et al. Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin. Clin. Cancer Res. 10, 6094–6100 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Sabbatini, P. J. et al. Immunization of ovarian cancer patients with a synthetic Lewis(Y)–protein conjugate vaccine: A phase 1 trial. Int. J. Cancer 87, 79–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Vandintherjanssen, A., Pals, S. T., Scheper, R., Breedveld, F. & Meijer, C. Dendritic cells and high endothelial venules in the rheumatoid synovial–membrane. J. Rhematol. 17, 11–17 (1990).

    CAS  Google Scholar 

  121. Salmi, M., Granfors, K., Macdermott, R. & Jalkanen, S. Aberrant binding of lamina propria lymphocytes to vascular endothelium in inflammatory bowel diseases. Gastroenterology 106, 596–605 (1994).

    Article  CAS  PubMed  Google Scholar 

  122. Salmi, M. & Jalkanen, S. Regulation of L-selectin expression on cultured bone-marrow leukocytes and their precursors. Eur. J. Immunol. 22, 835–843 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Duijvestijn, A. M., Kerkhove, M., Bargatze, R. F. & Butcher, E. C. Lymphoid tissue-specific and inflammation-specific endothelial-cell differentiation defined by monoclonal-antibodies. J. Immunol. 138, 713–719 (1987).

    CAS  PubMed  Google Scholar 

  124. Toppila, S., Paavonen, T., Laitinen, A., Laitinen, L. A. & Renkonen, R. Endothelial sulfated sialyl Lewis X glycans, putative L-selectin ligands, are preferentially expressed in bronchial asthma but not in other chronic inflammatory lung diseases. Am. J. Respir. Cell Mol. Biol. 23, 492–498 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Hanninen, A. et al. Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid-cell binding to islet endothelium. J. Clin. Invest. 92, 2509–2515 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Turunen, J. P. et al. De-novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(X) during cardiac transplant rejection- superior capacity of a tetravalent sialyl Lewis(X) oligosaccharide in inhibiting L-selectin–dependent lymphocyte adhesion. J. Exp. Med. 182, 1133–1141 (1995).

    Article  CAS  PubMed  Google Scholar 

  127. Slovin, S. et al. Multivalency in a phase II prostate cancer (PC) vaccine trial: Are more antigens better? Proc. Am. Soc. Clin. Oncol. 22, 167 (2003).

    Google Scholar 

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Acknowledgements

We thank J. Prescher, M. Paulick, I. Miller and S. Laughlin for critical reading of the manuscript.

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Correspondence to Carolyn R. Bertozzi.

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DATABASES

Entrez Gene

E-selectin

GlcNAc-TV

L-selectin

MUC1

MUC16

prostate-specific antigen

P-selectin

ST3Gal1

OMIM

Arthritis

asthma

diabetes

psoriasis

Glossary

GLYCOSYLTRANSFERASES

Enzymes that form glycosidic bonds between monosaccharide units.

GLYCOSIDASES

Enzymes that cleave glycosidic bonds.

LECTINS

Carbohydrate-binding proteins.

NEOEXPRESSION

Expression on adult tissues, when expression is normally restricted to embryonic tissues.

GANGLIOSIDE

A glycosphingolipid-containing sialic acid.

PASSIVE IMMUNIZATION

Treatment with an antibody, not actively recruiting the animal's immune response.

MICROHETEROGENEITY

Combination of structures.

SELECTINS

A family of carbohydrate-binding proteins (lectins) expressed on activated platelets (P-selectin) and endothelial cells (P- and E-selectin).

BIOORTHOGONAL FUNCTIONAL GROUP

A chemical moiety that reacts selectively with a reaction partner in a physiological environment yet is inert to the biological milieu.

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Dube, D., Bertozzi, C. Glycans in cancer and inflammation — potential for therapeutics and diagnostics. Nat Rev Drug Discov 4, 477–488 (2005). https://doi.org/10.1038/nrd1751

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