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Cell Surface Associated Alpha-l-Fucose Moieties Modulate Human Breast Cancer Neoplastic Progression

  • Original Paper
  • Published:
Pathology & Oncology Research

Abstract

Glycosylation drives critical processes important for mammalian cell–cell and cell–matrix interactions. Alpha-l-fucose (α-l-f) is a key monosaccharide component of oligosaccharides that has been found to be overexpressed during tumor progression. Modification of cell surface fucosylation, we hypothesized, alters tumor cell phenotype and function at the end of the neoplastic progression cascade including tumor invasion. Alpha-l-fucosidase (α-l-fase) is a glycosidase that specifically removes (α-l-f) from oligosaccharide sites. We first verified the effectiveness of the α-l-fase to specifically decrease the level of α-l-f on the cell surface of several human breast cancer cell lines and also examined the recovery time for these cells to repopulate their surfaces. To investigate the potential effect of defucosylation on tumor functions, we studied the proliferation, and invasion in vitro of human breast cancer MDA-MB-231 cells as the representative cell model. We further examined several fucose-associated molecules previously shown to be involved in tumor progression, including CD44 and CD15 (Lewis X antigen). We found that α-l-fase pretreatment significantly decreased the invasive capability of breast cancer cells. Deoxyfuconojirimycin (DFJ), a specific α-l-fase inhibitor, reversed this effect. After fucosidase treatment, the level of both CD15 and CD44 were found to be reduced as measured by flow cytometry. α-l-fase treatment, further, did not affect tumor cell proliferation in vitro under identical experimental conditions. Gelatin zymography of conditioned media from tumor cells treated with α-l-fase demonstrated no change in MMP-2 activity while MMP-9 was significantly reduced. In summary, fucose containing glycans were found widely distributed on the cell surface of breast cancer cells and could be effectively removed by α-l-fase treatment. This decreased fucosylation, in turn, was seen to impair the interaction between tumor cells and extracellular matrices, and thus affected key cell functions modulating tumor invasion. Further elucidation of the molecular pathways involved in the inhibition of tumor cell invasion may suggest a rationale for the use of glycobiologic therapeutics to deter tumor progression.

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Abbreviations

α-l-f:

alpha-l-fucose

α-l-fase:

alpha-l-fucosidase

BSA:

bovine serum albumin

FucT:

fucosyltransferase

Lotus :

Lotus tetragonolobus purpureaus

MMP:

matrix metalloproteinase

PBS:

phosphate-buffered saline

PE:

phycoerythrin

sLea:

sialyl Lewis A

sLex:

sialyl Lewis X

Ulex :

Ulex europaeus agglutinin I

TBST:

Tris-buffered saline with Tween

References

  1. Dennis JW, Granovsky M, Warren CE (1999) Glycoprotein glycosylation and cancer progression. Biochim Biophys Acta 1473(1):21–34

    PubMed  CAS  Google Scholar 

  2. Listinsky JJ, Listinsky CM, Alapati V, et al (2001) Cell surface fucose ablation as a therapeutic strategy for malignant neoplasms. Adv Anat Pathol 8(6):330–337

    Article  PubMed  CAS  Google Scholar 

  3. Mackinnon WB, Delbridge L, Russell P, et al (1996) Two-dimensional proton magnetic resonance spectroscopy for tissue characterization of thyroid neoplasms. World J Surg 20(7):841–847

    Article  PubMed  CAS  Google Scholar 

  4. Mackinnon WB, Russell P, May GL, et al (1995) Characterization of human ovarian epithelial tumors (ex vivo) by proton magnetic resonance spectroscopy. Int J Gynecol Cancer 5(3):211–221

    Article  PubMed  Google Scholar 

  5. Fernandez-Rodriguez J, Paez de la Cadena M, Martinez-Zorzono VS, et al (1997) Fucose levels in sera and in tumours of colorectal adenocarcinoma patients. Cancer Lett 121(2):147–153

    Article  PubMed  CAS  Google Scholar 

  6. Huang W, Li X (2000) Significance of fucose expression in lung carcinoma and their brain metastases. Zhonghua Bing Li Xue Za Zhi 29(4):259–262

    PubMed  CAS  Google Scholar 

  7. Patel PS, Baxi BR, Adhvaryu SG, et al (1990) Evaluation of serum sialic acid, heat stable alkaline phosphatase and fucose as markers of breast carcinoma. Anticancer Res 10(4):1071–1074

    PubMed  CAS  Google Scholar 

  8. Isacke CM, Yarwood H (2002) The hyaluronan receptor, CD44. Int J Biochem Cell Biol 34(7):718–721

    Article  PubMed  CAS  Google Scholar 

  9. Bourguignon LY (2001) CD44-mediated oncogenic signaling and cytoskeleton activation during mammary tumor progression. J Mammary Gland Biol Neoplasia 6(3):287–297

    Article  PubMed  CAS  Google Scholar 

  10. Stetler-Stevenson WG (2001) The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am 10(2):383–392

    PubMed  CAS  Google Scholar 

  11. Makita M (1991) [Relationship between the prognosis and the morphology of stromal invasion of the breast cancer]. Nippon Geka Gakkai Zasshi 92(8):1001–1009

    PubMed  CAS  Google Scholar 

  12. van 't Veer LJ Dai H, van de Vijver MJ, et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  Google Scholar 

  13. Nishimura Y (2003) gem-Diamine 1-N-iminosugars and related iminosugars, candidate of therapeutic agents for tumor metastasis. Curr Top Med Chem 3(5):575–591

    Article  PubMed  CAS  Google Scholar 

  14. Siegal GP Wang MJ, Rinehart CA, et al (1993) Development of a novel human extracellular matrix for quantitation of the invasiveness of human cells. Cancer Lett 69(2):123–132

    Article  Google Scholar 

  15. Singh RK Rinehart CA, Kim JP, et al (1996) Tumor cell invasion of basement membrane in vitro is regulated by amino acids. Cancer Invest 14(1):6–18

    Article  Google Scholar 

  16. Schwartz GG Wang MH, Zang M, et al (1997) 1 α,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol Biomarkers Prev 6(9):727–732

    Google Scholar 

  17. Winchester B Barker C, Baines S, et al. (1990) Inhibition of alpha-L-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin. Biochem J 265(1):277–282

    Google Scholar 

  18. Orntoft TF, Vestergaard EM (1999) Clinical aspects of altered glycosylation of glycoproteins in cancer. Electrophoresis 20(2):362–371

    Article  PubMed  CAS  Google Scholar 

  19. Couldrey C, Green JE (2000) Metastases: the glycan connection. Breast Cancer Res 2(5):321–323

    Article  PubMed  CAS  Google Scholar 

  20. Laidler P, Litynska A (1997) Tumor cell N-glycans in metastasis. Acta Biochim Pol 44(2):343–357

    PubMed  CAS  Google Scholar 

  21. Ono M, Hakomori S (2004) Glycosylation defining cancer cell motility and invasiveness. Glycoconj J 20(1):71–78

    Article  PubMed  CAS  Google Scholar 

  22. Carcel-Trullols J Stanley JS, Saha R, et al (2006) Characterization of the glycosylation profile of the human breast cancer cell line, MDA-231, and a bone colonizing variant. Int J Oncol 28(5):1173–1183

    Google Scholar 

  23. Takahashi N Iwahori A, Breitmon TR, et al (1997) Tunicamycin in combination with retinoic acid synergistically inhibits cell growth while decreasing palmitoylation and enhancing retinoylation of proteins in the human breast cancer cell line MCF-7. Oncol Res 9(10):527–533

    Google Scholar 

  24. Carlberg M Dricu A, Blegen H, et al (1996) Short exposures to tunicamycin induce apoptosis in SV40-transformed but not in normal human fibroblasts. Carcinogenesis 17(12):2589–2596

    Article  Google Scholar 

  25. Ciolczyk-Wierzbicka D, Amoresano A, Casbarr A, et al (2004) The structure of the oligosaccharides of N-cadherin from human melanoma cell lines. Glycoconj J 20(7–8):483–492

    PubMed  CAS  Google Scholar 

  26. Becker DJ, Lowe JB (2003) Fucose: biosynthesis and biological function in mammals. Glycobiology 13(7):41R–53R

    Article  PubMed  CAS  Google Scholar 

  27. Kiricuta I, Bojan O, Comes R, et al (1979) Significance of serum fucose, sialic acid, haptoglobine and phospholipids levels in the evolution and treatment of breast cancer. Arch zeschwulstforsch 49(2):106–112

    CAS  Google Scholar 

  28. Natsume A, Wakitani M, Yamane-Ohnuki N, et al (2005) Fucose removal from complex-type oligosaccharide enhances the antibody-dependent cellular cytotoxicity of single-gene-encoded antibody comprising a single-chain antibody linked the antibody constant region. J Immunol Methods 306(1–2):93–103

    Article  PubMed  CAS  Google Scholar 

  29. Thompson S Cantwell BM, Matta KI, et al. (1992) Parallel changes in the blood levels of abnormally-fucosylated haptoglobin and alpha 1,3 fucosyltransferase in relationship to tumour burden: more evidence for a disturbance of fucose metabolism in cancer. Cancer Lett 65(2):115–121

    Article  Google Scholar 

  30. Ding KF, Zheng S (2004) Study on relationship of fucosyltransferase gene types in breast cancer with metastasis and prognosis. Zhonghua Wai Ke Za Zhi 42(9):546–550

    PubMed  Google Scholar 

  31. Hiller KM Mayben JP, Bendt KM et al (2000) Transfection of alpha(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells. Mol Carcinog 27(4):280–288

    Article  Google Scholar 

  32. Liu F Zhang Y, Zhang XY, et al (2002) Transfection of the nm23-H1 gene into human hepatocarcinoma cell line inhibits the expression of sialyl Lewis X, alpha1,3 fucosyltransferase VII, and metastatic potential. J Cancer Res Clin Oncol 128(4):189–196

    Article  Google Scholar 

  33. Hakomori S (2002) Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci USA 99(16):10231–10233

    Article  PubMed  CAS  Google Scholar 

  34. Johnson SW, Alhadeff JA (1991) Mammalian alpha-L-fucosidases. Comp Biochem Physiol B 99(3):479–488

    Article  PubMed  CAS  Google Scholar 

  35. Fernandez-Rodriguez J, Ayude D, de la Cadena MP, et al (2000) Alpha-L-fucosidase enzyme in the prediction of colorectal cancer patients at high risk of tumor recurrence. Cancer Detect Prev 24(2):143–149

    PubMed  CAS  Google Scholar 

  36. Hakomori S (2001) Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. Adv Exp Med Biol 491:369–402

    PubMed  CAS  Google Scholar 

  37. Capurro M Ballore C, Bover L, et al. (1999) Differential lytic and agglutinating activity of the anti-Lewis(x) monoclonal antibody FC-2.15 on human polymorphonuclear neutrophils and MCF-7 breast tumor cells. In vitro and ex vivo studies. Cancer Immunol Immunother 48(2–3):100–108

    Article  Google Scholar 

  38. Gu H, Ni C, Zhan R (2000) The expression of CD15 mRNA CD44v6 mRNA and nm23H1 mRNA in breast cancer and their clinical significance. Zhonghua Yi Xue Za Zhi 80(11):854–857

    PubMed  CAS  Google Scholar 

  39. Brooks SA, Leathem AJ (1995) Expression of the CD15 antigen (Lewis x) in breast cancer. Histochem J 27(9):689–693

    PubMed  CAS  Google Scholar 

  40. Madjd Z Parsons T, Watson NF, et al. (2005) High expression of Lewis y/b antigens is associated with decreased survival in lymph node negative breast carcinomas. Breast Cancer Res 7(5):R780–787

    Article  Google Scholar 

  41. Nakagoe T, Fukushima K, Tuji T, et al. (1998) Immunohistochemical expression of ABH/Lewis-related antigens in primary breast carcinomas and metastatic lymph node lesions. Cancer Detect Prev 22(6):499–505

    Article  PubMed  CAS  Google Scholar 

  42. Reitman ML, Trowbridge IS, Kornfeld S (1980) Mouse lymphoma cell lines resistant to pea lectin are defective in fucose metabolism. J Biol Chem 255(20):9900–9906

    PubMed  CAS  Google Scholar 

  43. Ripka JA, Adamany A, Stanley P (1986) Two Chinese hamster ovary glycosylation mutants affected in the conversion of GDP-mannose to GDP-fucose. Arch Biochem Biophys 249(2):533–545

    Article  PubMed  CAS  Google Scholar 

  44. Dabelsteen E (2002) ABO blood group antigens in oral mucosa. What is new?. J Oral Pathol Med, 31(2):65–70

    CAS  Google Scholar 

  45. Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189(2):161–168

    Article  PubMed  CAS  Google Scholar 

  46. Morini M, Mottolese M, Ferrari N, et al (2000) The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer 87(3):336–342

    Article  PubMed  CAS  Google Scholar 

  47. Xiong L, Andrews D, Regnier F (2003) Comparative proteomics of glycoproteins based on lectin selection and isotope coding. J Proteome Res 2(6):618–625

    Article  PubMed  CAS  Google Scholar 

  48. Gasbarri A, Del Prete F, Girnita L, et al (2003) CD44s adhesive function spontaneous and PMA-inducible CD44 cleavage are regulated at post-translational level in cells of melanocytic lineage. Melanoma Res 13(4):325–337

    Article  PubMed  CAS  Google Scholar 

  49. Catterall JB, Jones LM, Turner GA (1999) Membrane protein glycosylation and CD44 content in the adhesion of human ovarian cancer cells to hyaluronan. Clin Exp Metastasis 17(7):583–591

    Article  PubMed  CAS  Google Scholar 

  50. Skelton TP Zeng C, Nocks A, et al. (1998) Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan. J Cell Biol 140(2):431–446

    Article  Google Scholar 

  51. Bourguignon LY, Zhu D, Zhu H (1998) CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression. Front Biosci 3:d637–d649

    PubMed  CAS  Google Scholar 

  52. Matsuki H, Yonezawa K, Obata K, et al. (2003) Monoclonal antibodies with defined recognition sequences in the stem region of CD44: detection of differential glycosylation of CD44 between tumor and stromal cells in tissue. Cancer Res, 63(23):8278–8283

    CAS  Google Scholar 

  53. Hakomori S (2004) Glycosynapses: microdomains controlling carbohydrate-dependent cell adhesion and signaling. An Acad Bras Cienc 76(3):553–572

    PubMed  CAS  Google Scholar 

  54. Evans E Leung A, Heinrich V, et al. (2004) Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond. Proc Natl Acad Sci U SA 101(31):11281–11286

    Article  Google Scholar 

  55. Rampal R, Arboleda-Velsquez JF, Nita-Lazar A, et al (2005) Highly conserved O-fucose sites have distinct effects on Notch1 function. J Biol Chem 280(37):32133–32140

    Article  PubMed  CAS  Google Scholar 

  56. Schachter H (2005) The search for glycan function: fucosylation of the TGF-beta1 receptor is required for receptor activation. Proc Natl Acad Sci U S A 102(44):15721–15722

    Article  PubMed  CAS  Google Scholar 

  57. Gornik O Dumic J, Flogel M, et al (2006) Glycoscience—a new frontier in rational drug design. Acta Pharm 56(1):19–30

    Google Scholar 

  58. Kannagi R (1997) Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J, 14(5):577–584

    Article  CAS  Google Scholar 

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Acknowledgement

Grant support

Supported in part by grants from the DOD [DAMD 17-99-1-9415] and the NIH [P50 CA89019; R21 AT001636, HHSN2-61200566001C (SBIR Phase II, RPF N44-CM-47041-19), and HL62736

Conflict of interest statement

Drs. Singh and Siegal hold intellectual property rights for HuBiogel™ (US Patent No. 10/546,506 [Patent Pending], International Application No. PCT/US2004/005255 [Patent Pending] to the UAB Research Foundation. Additionally, Dr. Singh is the CEO of In Vivo Biosciences, Inc., which holds the exclusive worldwide rights to market this biomaterial. All other authors have declared that they have no other real or potential conflict of interest associated with this manuscript.

Author information

Author notes

  1. Catherine M. Listinsky

    Present address: Department of Pathology, Case-Western Reserve University School of Medicine, Cleveland, OH, USA

  2. Raj K. Singh

    Present address: Vivo Biosciences, Inc., Birmingham, AL, USA

  3. Jay J. Listinsky

    Present address: Department of Radiology, Case-Western Reserve University School of Medicine, Cleveland, OH, USA

Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Kun Yuan, Catherine M. Listinsky, Raj K. Singh & Gene P. Siegal

  2. Department of Diagnostic Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Jay J. Listinsky

  3. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Gene P. Siegal

  4. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Gene P. Siegal

  5. Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, KB 506, 619 19th St. South, Birmingham, AL, 35233, USA

    Gene P. Siegal

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  1. Kun Yuan
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Correspondence to Gene P. Siegal.

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Yuan, K., Listinsky, C.M., Singh, R.K. et al. Cell Surface Associated Alpha-l-Fucose Moieties Modulate Human Breast Cancer Neoplastic Progression. Pathol. Oncol. Res. 14, 145–156 (2008). https://doi.org/10.1007/s12253-008-9036-x

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