Sialylation and Immune Surveillance of Cancer by Siglecs

  • Bindu Mohan
  • Paul R. CrockerEmail author


Changes in cell surface glycosylation are a key feature of cancer initiation and progression. Sialic acid is a major glycan attached to extracellular proteins and lipids. Altered sialylation in cancer can impact at many levels and may result in improved cancer cell survival and spread. Here we focus on sialic acid-dependent interactions of tumour cells with sialic acid-binding Ig-like lectins (siglecs). These proteins are expressed broadly in the immune system and can modulate cellular functions in diverse ways. We discuss changes in sialylation commonly observed in tumours and the emerging role of siglecs in modulating both host immune responses and tumour responses.


Sialic acid Cancer Glycosylation Lectins Siglec Immune system 


  1. Belisle JA, Horibata S, Jennifer GA, Petrie S, Kapur A, Andre S, Gabius HJ, Rancourt C, Connor J, Paulson JC, Patankar MS (2010) Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes. Mol Cancer 9:118. doi: 10.1186/1476-4598-9-118 PubMedCentralCrossRefPubMedGoogle Scholar
  2. Birks SM, Danquah JO, King L, Vlasak R, Gorecki DC, Pilkington GJ (2011) Targeting the GD3 acetylation pathway selectively induces apoptosis in glioblastoma. Neuro Oncol 13(9):950–960. doi: 10.1093/neuonc/nor108nor108 [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  3. Bobowski M, Vincent A, Steenackers A, Colomb F, Van Seuningen I, Julien S, Delannoy P (2013) Estradiol represses the G(D3) synthase gene ST8SIA1 expression in human breast cancer cells by preventing NFkappaB binding to ST8SIA1 promoter. PLoS One 8(4):e62559. doi: 10.1371/journal.pone.0062559PONE-D-12-26811 [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  4. Cao H, Crocker PR (2011) Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation? Immunology 132(1):18–26. doi: 10.1111/j.1365-2567.2010.03368.x PubMedCentralCrossRefPubMedGoogle Scholar
  5. Cazet A, Julien S, Bobowski M, Burchell J, Delannoy P (2010) Tumour-associated carbohydrate antigens in breast cancer. Breast Cancer Res 12(3):204. doi: 10.1186/bcr2577 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Christiansen MN, Chik J, Lee L, Anugraham M, Abrahams JL, Packer NH (2013) Cell surface protein glycosylation in cancer. Proteomics. doi: 10.1002/pmic.201300387 Google Scholar
  7. Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC (2004) Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact. Proc Natl Acad Sci U S A 101(16):6104–6109. doi: 10.1073/pnas.04008511010400851101 [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  8. Crocker PR, Clark EA, Filbin M, Gordon S, Jones Y, Kehrl JH, Kelm S, Le Douarin N, Powell L, Roder J, Schnaar RL, Sgroi DC, Stamenkovic K, Schauer R, Schachner M, van den Berg TK, van der Merwe PA, Watt SM, Varki A (1998) Siglecs: a family of sialic-acid binding lectins. Glycobiology 8(2):vCrossRefPubMedGoogle Scholar
  9. Crocker PR, Paulson JC, Varki A (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7(4):255–266. doi: 10.1038/nri2056, nri2056 [pii]CrossRefPubMedGoogle Scholar
  10. Daniotti JL, Iglesias-Bartolome R (2011) Metabolic pathways and intracellular trafficking of gangliosides. IUBMB Life 63(7):513–520. doi: 10.1002/iub.477 CrossRefPubMedGoogle Scholar
  11. Gomes C, Osorio H, Pinto MT, Campos D, Oliveira MJ, Reis CA (2013) Expression of ST3GAL4 leads to SLe(x) expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells. PLoS One 8(6), e66737. doi: 10.1371/journal.pone.0066737PONE-D-13-02396 [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  12. Gu J, Taniguchi N (2004) Regulation of integrin functions by N-glycans. Glycoconj 8(4):e62559. doi: 10.1023/B:GLYC.0000043741.47559.30, 5277444 [pii]Google Scholar
  13. Gubbels JA, Felder M, Horibata S, Belisle JA, Kapur A, Holden H, Petrie S, Migneault M, Rancourt C, Connor JP, Patankar MS (2010) MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Mol Cancer 9:11. doi: 10.1186/1476-4598-9-111476-4598-9-11 [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  14. Handa K, Hakomori SI (2012) Carbohydrate to carbohydrate interaction in development process and cancer progression. Glycoconj J 29(8–9):627–637. doi: 10.1007/s10719-012-9380-7 CrossRefPubMedGoogle Scholar
  15. Holst S, Stavenhagen K, Balog CI, Koeleman CA, McDonnell LM, Mayboroda OA, Verhoeven A, Mesker WE, Tollenaar RA, Deelder AM, Wuhrer M (2013) Investigations on aberrant glycosylation of glycosphingolipids in colorectal cancer tissues using liquid chromatography and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). Mol Cell Proteomics 12(11):3081–3093. doi: 10.1074/mcp.M113.030387 PubMedCentralCrossRefPubMedGoogle Scholar
  16. Hudak JE, Canham SM, Bertozzi CR (2014) Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat Chem Biol 10(1):69–75. doi: 10.1038/nchembio.1388 PubMedCentralCrossRefPubMedGoogle Scholar
  17. Ito H, Hiraiwa N, Sawada-Kasugai M, Akamatsu S, Tachikawa T, Kasai Y, Akiyama S, Ito K, Takagi H, Kannagi R (1997) Altered mRNA expression of specific molecular species of fucosyl- and sialyl-transferases in human colorectal cancer tissues. Int J Cancer 71(4):556–564. doi: 10.1002/(SICI)1097-0215(19970516)71:4<556::AID-IJC9>3.0.CO;2-T [pii]CrossRefPubMedGoogle Scholar
  18. Julien S, Lagadec C, Krzewinski-Recchi MA, Courtand G, Le Bourhis X, Delannoy P (2005) Stable expression of sialyl-Tn antigen in T47-D cells induces a decrease of cell adhesion and an increase of cell migration. Breast Cancer Res Treat 90(1):77–84. doi: 10.1007/s10549-004-3137-3 CrossRefPubMedGoogle Scholar
  19. Kawasaki Y, Ito A, Withers DA, Taima T, Kakoi N, Saito S, Arai Y (2010) Ganglioside DSGb5, preferred ligand for Siglec-7, inhibits NK cell cytotoxicity against renal cell carcinoma cells. Glycobiology 20(11):1373–1379. doi: 10.1093/glycob/cwq116 CrossRefPubMedGoogle Scholar
  20. Kidder D, Richards HE, Ziltener HJ, Garden OA, Crocker PR (2013) Sialoadhesin ligand expression identifies a subset of CD4 + Foxp3- T cells with a distinct activation and glycosylation profile. J Immunol 190(6):2593–2602. doi: 10.4049/jimmunol.1201172 PubMedCentralCrossRefPubMedGoogle Scholar
  21. Klaas M, Crocker PR (2012) Sialoadhesin in recognition of self and non-self. Semin Immunopathol 34(3):353–364. doi: 10.1007/s00281-012-0310-3 CrossRefPubMedGoogle Scholar
  22. Klaas M, Oetke C, Lewis LE, Erwig LP, Heikema AP, Easton A, Willison HJ, Crocker PR (2012) Sialoadhesin promotes rapid proinflammatory and type I IFN responses to a sialylated pathogen, Campylobacter jejuni. J Immunol 189(5):2414–2422. doi: 10.4049/jimmunol.1200776 PubMedCentralCrossRefPubMedGoogle Scholar
  23. Kniep B, Kniep E, Ozkucur N, Barz S, Bachmann M, Malisan F, Testi R, Rieber EP (2006) 9-O-acetyl GD3 protects tumor cells from apoptosis. Int J Cancer 119(1):67–73. doi: 10.1002/ijc.21788 CrossRefPubMedGoogle Scholar
  24. Lopez PH, Schnaar RL (2009) Gangliosides in cell recognition and membrane protein regulation. Curr Opin Struct Biol 19(5):549–557. doi: 10.1016/ [pii]PubMedCentralCrossRefPubMedGoogle Scholar
  25. Mitic N, Milutinovic B, Jankovic M (2012) Assessment of sialic acid diversity in cancer- and non-cancer related CA125 antigen using sialic acid-binding Ig-like lectins (Siglecs). Dis Markers 32(3):187–194. doi: 10.3233/DMA-2011-0872 PubMedCentralCrossRefPubMedGoogle Scholar
  26. Miyazaki K, Ohmori K, Izawa M, Koike T, Kumamoto K, Furukawa K, Ando T, Kiso M, Yamaji T, Hashimoto Y, Suzuki A, Yoshida A, Takeuchi M, Kannagi R (2004) Loss of disialyl Lewis(a), the ligand for lymphocyte inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) associated with increased sialyl Lewis(a) expression on human colon cancers. Cancer Res 64(13):4498–4505. doi: 10.1158/0008-5472.CAN-03-3614 CrossRefPubMedGoogle Scholar
  27. Miyazaki K, Sakuma K, Kawamura YI, Izawa M, Ohmori K, Mitsuki M, Yamaji T, Hashimoto Y, Suzuki A, Saito Y, Dohi T, Kannagi R (2012) Colonic epithelial cells express specific ligands for mucosal macrophage immunosuppressive receptors siglec-7 and −9. J Immunol 188(9):4690–4700. doi: 10.4049/jimmunol.1100605 CrossRefPubMedGoogle Scholar
  28. Nath D, Hartnell A, Happerfield L, Miles DW, Burchell J, Taylor-Papadimitriou J, Crocker PR (1999) Macrophage-tumour cell interactions: identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin. Immunology 98(2):213–219PubMedCentralCrossRefPubMedGoogle Scholar
  29. Nicoll G, Avril T, Lock K, Furukawa K, Bovin N, Crocker PR (2003) Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and -independent mechanisms. Eur J Immunol 33(6):1642–1648. doi: 10.1002/eji.200323693 CrossRefPubMedGoogle Scholar
  30. Ohnishi K, Komohara Y, Saito Y, Miyamoto Y, Watanabe M, Baba H, Takeya M (2013) CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer Sci 104(9):1237–1244. doi: 10.1111/cas.12212 CrossRefPubMedGoogle Scholar
  31. Ohta M, Ishida A, Toda M, Akita K, Inoue M, Yamashita K, Watanabe M, Murata T, Usui T, Nakada H (2010) Immunomodulation of monocyte-derived dendritic cells through ligation of tumor-produced mucins to Siglec-9. Biochem Biophys Res Commun 402(4):663–669. doi: 10.1016/j.bbrc.2010.10.079 CrossRefPubMedGoogle Scholar
  32. Oliva JP, Valdes Z, Casaco A, Pimentel G, Gonzalez J, Alvarez I, Osorio M, Velazco M, Figueroa M, Ortiz R, Escobar X, Orozco M, Cruz J, Franco S, Diaz M, Roque L, Carr A, Vazquez AM, Mateos C, Rubio MC, Perez R, Fernandez LE (2006) Clinical evidences of GM3 (NeuGc) ganglioside expression in human breast cancer using the 14F7 monoclonal antibody labelled with (99m)Tc. Breast Cancer Res Treat 96(2):115–121. doi: 10.1007/s10549-005-9064-0 CrossRefPubMedGoogle Scholar
  33. Padler-Karavani V (2013) Aiming at the sweet side of cancer: aberrant glycosylation as possible target for personalized-medicine. Cancer Lett. doi: 10.1016/j.canlet.2013.10.005 PubMedGoogle Scholar
  34. Park JJ, Lee M (2013) Increasing the alpha 2, 6 sialylation of glycoproteins may contribute to metastatic spread and therapeutic resistance in colorectal cancer. Gut Liver 7(6):629–641. doi: 10.5009/gnl.2013.7.6.629 PubMedCentralCrossRefPubMedGoogle Scholar
  35. Rabinovich GA, Croci DO (2012) Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity 36(3):322–335. doi: 10.1016/j.immuni.2012.03.004 CrossRefPubMedGoogle Scholar
  36. Richards DM, Hettinger J, Feuerer M (2013) Monocytes and macrophages in cancer: development and functions. Cancer Microenviron 6(2):179–191. doi: 10.1007/s12307-012-0123-x PubMedCentralCrossRefPubMedGoogle Scholar
  37. Sabit I, Hashimoto N, Matsumoto Y, Yamaji T, Furukawa K (2013) Binding of a sialic acid-recognizing lectin Siglec-9 modulates adhesion dynamics of cancer cells via calpain-mediated protein degradation. J Biol Chem 288(49):35417–35427. doi: 10.1074/jbc.M113.513192 PubMedCentralCrossRefPubMedGoogle Scholar
  38. Saunderson SC, Dunn AC, Crocker PR, McLellan AD (2014) CD169 mediates the capture of exosomes in spleen and lymph node. Blood 123(2):208–216. doi: 10.1182/blood-2013-03-489732 PubMedCentralCrossRefPubMedGoogle Scholar
  39. Seales EC, Jurado GA, Singhal A, Bellis SL (2003) Ras oncogene directs expression of a differentially sialylated, functionally altered beta1 integrin. Oncogene 22(46):7137–7145. doi: 10.1038/sj.onc.12068341206834 [pii]CrossRefPubMedGoogle Scholar
  40. Seales EC, Jurado GA, Brunson BA, Wakefield JK, Frost AR, Bellis SL (2005) Hypersialylation of beta1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility. Cancer Res 65(11):4645–4652. doi: 10.1158/0008-5472.CAN-04-3117, 65/11/4645 [pii]CrossRefPubMedGoogle Scholar
  41. Shen Y, Kohla G, Lrhorfi AL, Sipos B, Kalthoff H, Gerwig GJ, Kamerling JP, Schauer R, Tiralongo J (2004) O-acetylation and de-O-acetylation of sialic acids in human colorectal carcinoma. Eur J Biochem 271(2):281–290CrossRefPubMedGoogle Scholar
  42. Takamiya R, Ohtsubo K, Takamatsu S, Taniguchi N, Angata T (2013) The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-beta secretion from monocytes/macrophages through the DAP12-Syk pathway. Glycobiology 23(2):178–187. doi: 10.1093/glycob/cws139 CrossRefPubMedGoogle Scholar
  43. Tanida S, Akita K, Ishida A, Mori Y, Toda M, Inoue M, Ohta M, Yashiro M, Sawada T, Hirakawa K, Nakada H (2013) Binding of the sialic acid-binding lectin, Siglec-9, to the membrane mucin, MUC1, induces recruitment of beta-catenin and subsequent cell growth. J Biol Chem 288(44):31842–31852. doi: 10.1074/jbc.M113.471318 PubMedCentralCrossRefPubMedGoogle Scholar
  44. Toda M, Akita K, Inoue M, Taketani S, Nakada H (2008) Down-modulation of B cell signal transduction by ligation of mucins to CD22. Biochem Biophys Res Commun 372(1):45–50. doi: 10.1016/j.bbrc.2008.04.175 CrossRefPubMedGoogle Scholar
  45. Toda M, Hisano R, Yurugi H, Akita K, Maruyama K, Inoue M, Adachi T, Tsubata T, Nakada H (2009) Ligation of tumour-produced mucins to CD22 dramatically impairs splenic marginal zone B-cells. Biochem J 417(3):673–683. doi: 10.1042/BJ20081241 CrossRefPubMedGoogle Scholar
  46. Varki A (1993) Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3(2):97–130CrossRefPubMedGoogle Scholar
  47. Varki A, Schauer R et al (2009) Sialic acids. In: Varki A, Cummings RD, Esko JD (eds) Essentials of glycobiology, 2nd edn. Cold Spring Harbor, New YorkGoogle Scholar
  48. Yang JM, Byrd JC, Siddiki BB, Chung YS, Okuno M, Sowa M, Kim YS, Matta KL, Brockhausen I (1994) Alterations of O-glycan biosynthesis in human colon cancer tissues. Glycobiology 4(6):873–884CrossRefPubMedGoogle Scholar
  49. Yu RK, Tsai YT, Ariga T, Yanagisawa M (2011) Structures, biosynthesis, and functions of gangliosides--an overview. J Oleo Sci 60(10):537–544, doi:JST.JSTAGE/jos/60.537 [pii]PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  1. 1.Division of Cell Signalling and Immunology, College of life SciencesUniversity of DundeeDundeeUK

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