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Roles of heparan-sulphate glycosaminoglycans in cancer

Nature Reviews Cancer volume 2, pages 521–528 (2002)Cite this article

Key Points

  • Heparan-sulphate glycosaminoglycans (HSGAGs) act at the cell–extracellular-matrix (ECM) interface to modulate cell signalling, thereby regulating how a cell perceives its environment.

  • HSGAGs interact with various extracellular signalling molecules: growth factors, morphogens, enzymes and chemokines. The specificity of these interactions is dependent on HSGAG sequence, spacing of binding sites and the three-dimensional structure of the HSGAG chain.

  • HSGAGs, depending on location and sequence, impinge on tumour onset and progression in various ways, some of which are pro-tumorigenic and others of which are anti-tumorigenic.

  • HSGAGs at the tumour-cell surface actively modulate the tumorigenic process by regulating autocrine signalling loops that lead to unregulated cell growth.

  • HSGAGs impinge on how an organism responds to a growing tumour, including the recruitment of cells of the immune system to the tumour site, formation of a fibrin shell around the tumour that acts as a protective barrier and development of new blood vessels to the site of the growing tumour.

  • Compelling clinical evidence indicates that pharmacological doses of heparin, a highly sulphated HSGAG, can have a marked effect on tumour metastasis. Clinical trials have been designed to determine the exact benefits of heparin therapy in cancer.

  • In addition, the low-molecular-weight heparins (LMWHs) — a series of heparin fragments that share many of heparin's activities, including its anticoagulant effect, but lack several of its side effects — might show even greater antitumour activity.

  • The advent of HSGAG sequencing technologies promises to usher in a new generation of LMWHs with potent antitumour activity.

Abstract

Cell-surface/extracellular-matrix heparan-sulphate glycosaminoglycans (HSGAGs) are complex polysaccharides that are ubiquitous in nature, and that regulate several aspects of cancer biology, including tumorigenesis, tumour progression and metastasis. Recently gained insights into the structure of HSGAGs have extended our understanding of their role in the oncogenic process. At present, clinical trials are examining the anticancer properties of exogenous highly sulphated HSGAGs, including heparin and low-molecular-weight heparins, in addition to small oligosaccharide heparin mimetics. Combined with our more intricate understanding of HSGAG structure, this emerging structure–activity approach opens exciting avenues for the generation of polysaccharide-based anticancer therapeutics.

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Figure 1: Structure and biology of heparan-sulphate glycosaminoglycans.
Figure 2: Role of heparan-sulphate glycosaminoglycans in tumour metastasis.

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References

  1. Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404, 725–728 (2000).

    Article  CAS  Google Scholar 

  2. Conrad, H. E. Heparin-Binding Proteins (Academic Press, San Diego, 1998).This book describes what is known about the structure and function of HSGAGs, as well as tools that have been developed to study structure–function relationships.

    Google Scholar 

  3. Liu, D., Shriver, Z., Qi, Y., Venkataraman, G. & Sasisekharan, R. Dynamic regulation of tumor growth and metastasis by heparan sulfate glycosaminoglycans. Semin. Thromb. Hemost. 28, 67–78 (2002).

    Article  CAS  Google Scholar 

  4. Gallagher, J. T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357–361 (2001).

    Article  CAS  Google Scholar 

  5. Esko, J. D. & Lindahl, U. Molecular diversity of heparan sulfate. J. Clin. Invest. 108, 169–173 (2001).

    Article  CAS  Google Scholar 

  6. Turnbull, J., Powell, A. & Guimond, S. Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends Cell Biol. 11, 75–82 (2001).

    Article  CAS  Google Scholar 

  7. Sasisekharan, R. & Venkataraman, G. Heparin and heparan sulfate: biosynthesis, structure and function. Curr. Opin. Chem. Biol. 4, 626–631 (2000).

    Article  CAS  Google Scholar 

  8. Faham, S., Linhardt, R. J. & Rees, D. C. Diversity does make a difference: fibroblast growth factor-heparin interactions. Curr. Opin. Struct. Biol. 8, 578–586 (1998).

    Article  CAS  Google Scholar 

  9. Jin, L. et al. The anticoagulant activation of antithrombin by heparin. Proc. Natl Acad. Sci. USA 94, 14683–14688 (1997).

    Article  CAS  Google Scholar 

  10. Schlessinger, J. et al. Crystal structure of a ternary FGF–FGFR–heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743–750 (2000).

    Article  CAS  Google Scholar 

  11. DiGabriele, A. D. et al. Structure of a heparin-linked biologically active dimer of fibroblast growth factor. Nature 393, 812–817 (1998).

    Article  CAS  Google Scholar 

  12. Mulloy, B. & Linhardt, R. J. Order out of complexity: protein structures that interact with heparin. Curr. Opin. Struct. Biol. 11, 623–628 (2001).

    Article  CAS  Google Scholar 

  13. Chang, Z., Meyer, K., Rapraeger, A. C. & Friedl, A. Differential ability of heparan sulfate proteoglycans to assemble the fibroblast growth factor receptor complex in situ. FASEB J. 14, 137–144 (2000).

    Article  CAS  Google Scholar 

  14. Nurcombe, V., Ford, M. D., Wildschut, J. A. & Bartlett, P. F. Developmental regulation of neural response to FGF1 and FGF2 by heparan sulfate proteoglycan. Science 260, 103–106 (1993).

    Article  CAS  Google Scholar 

  15. Dhoot, G. K. et al. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 293, 1663–1666 (2001).Shows that cells actively modulate their HSGAG coat to influence morphogen gradients and, therefore, pattern formation.

    Article  CAS  Google Scholar 

  16. Cosgrove, R. H., Zacharski, L. R., Racine, E. & Andersen, J. C. Improved cancer mortality with low-molecular-weight heparin treatment: a review of the evidence. Semin. Thromb. Hemost. 28, 79–88 (2002).

    Article  CAS  Google Scholar 

  17. Vlodavsky, I. & Friedmann, Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J. Clin. Invest. 108, 341–347 (2001).

    Article  CAS  Google Scholar 

  18. Varki, N. M. & Varki, A. Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Semin. Thromb. Hemost. 28, 53–66 (2002).

    Article  CAS  Google Scholar 

  19. Liu, D., Shriver, Z., Venkataraman, G., El Shabrawi, Y. & Sasisekharan, R. Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis. Proc. Natl Acad. Sci. USA 99, 568–573 (2002).Presents the novel observation that HSGAGs of differing structure can have opposing roles in mediating the processes of primary tumour growth and metastasis.

    Article  CAS  Google Scholar 

  20. Blackhall, F. H., Merry, C. L., Davies, E. J. & Jayson, G. C. Heparan sulfate proteoglycans and cancer. Br. J. Cancer 85, 1094–1098 (2001).

    Article  CAS  Google Scholar 

  21. Xiang, Y. Y., Ladeda, V. & Filmus, J. Glypican-3 expression is silenced in human breast cancer. Oncogene 20, 7408–7412 (2001).

    Article  CAS  Google Scholar 

  22. Filmus, J. Glypicans in growth control and cancer. Glycobiology 11, 19R–23R (2001).

    Article  CAS  Google Scholar 

  23. Sanderson, R. D. Heparan sulfate proteoglycans in invasion and metastasis. Semin. Cell Dev. Biol. 12, 89–98 (2001).

    Article  CAS  Google Scholar 

  24. Jayson, G. C. et al. Heparan sulfate undergoes specific structural changes during the progression from human colon adenoma to carcinoma in vitro. J. Biol. Chem. 273, 51–57 (1998).

    Article  CAS  Google Scholar 

  25. DeBaun, M. R., Ess, J. & Saunders, S. Simpson–Golabi–Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition. Mol. Genet. Metab. 72, 279–286 (2001).

    Article  CAS  Google Scholar 

  26. Mundhenke, C., Meyer, K., Drew, S. & Friedl, A. Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomas. Am. J. Pathol. 160, 185–194 (2002).

    Article  CAS  Google Scholar 

  27. Kreuger, J., Salmivirta, M., Sturiale, L., Gimenez-Gallego, G. & Lindahl, U. Sequence analysis of heparan sulfate epitopes with graded affinities for fibroblast growth factors 1 and 2. J. Biol. Chem. 276, 30744–30752 (2001).

    Article  CAS  Google Scholar 

  28. Iozzo, R. V. & San Antonio, J. D. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J. Clin. Invest. 108, 349–355 (2001).

    Article  CAS  Google Scholar 

  29. Folkman, J. Angiogenesis-dependent diseases. Semin. Oncol. 28, 536–542 (2001).

    Article  CAS  Google Scholar 

  30. Sasisekharan, R., Moses, M. A., Nugent, M. A., Cooney, C. L. & Langer, R. Heparinase inhibits neovascularization. Proc. Natl Acad. Sci. USA 91, 1524–1528 (1994).

    Article  CAS  Google Scholar 

  31. Karumanchi, S. A. et al. Cell surface glypicans are low-affinity endostatin receptors. Mol. Cell 7, 811–822 (2001).

    Article  CAS  Google Scholar 

  32. Smorenburg, S. M. & Van Noorden, C. J. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol. Rev. 53, 93–105 (2001).

    CAS  PubMed  Google Scholar 

  33. Tovari, J. et al. Role of sinusoidal heparan sulfate proteoglycan in liver metastasis formation. Int. J. Cancer 71, 825–831 (1997).

    Article  CAS  Google Scholar 

  34. Hulett, M. D. et al. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nature Med. 5, 803–809 (1999).

    Article  CAS  Google Scholar 

  35. Vlodavsky, I. et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nature Med. 5, 793–802 (1999).These two studies report the cloning and characterization of the human heparanase gene. Heparanase is an enzyme that is produced by cancer cells that was found to be a key factor or switch by which a tumour becomes metastatic. This has led to a substantial effort to identify inhibitors of human heparanase as a therapeutic strategy to combat metastasis.

    Article  CAS  Google Scholar 

  36. Kakkar, A. K. & Williamson, R. C. Antithrombotic therapy in cancer. BMJ 318, 1571–1572 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Zacharski, L. R., Ornstein, D. L. & Mamourian, A. C. Low-molecular-weight heparin and cancer. Semin. Thromb. Hemost. 26, 69–77 (2000).Definitive review of the effects of low-molecular-weight heparin on cancer progression.

    Article  CAS  Google Scholar 

  39. Goger, B. et al. Different affinities of glycosaminoglycan oligosaccharides for monomeric and dimeric interleukin-8: a model for chemokine regulation at inflammatory sites. Biochemistry 41, 1640–1646 (2002).

    Article  CAS  Google Scholar 

  40. Koopmann, W., Ediriwickrema, C. & Krangel, M. S. Structure and function of the glycosaminoglycan binding site of chemokine macrophage-inflammatory protein-1β. J. Immunol. 163, 2120–2127 (1999).

    CAS  PubMed  Google Scholar 

  41. Vlodavsky, I. et al. Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. Semin. Cancer Biol. 12, 121–129 (2002).

    Article  CAS  Google Scholar 

  42. Iversen, P. O., Sorensen, D. R. & Benestad, H. B. Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia 16, 376–381 (2002).

    Article  CAS  Google Scholar 

  43. Parish, C. R., Freeman, C., Brown, K. J., Francis, D. J. & Cowden, W. B. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 59, 3433–3441 (1999).

    CAS  PubMed  Google Scholar 

  44. Bentolila, A. et al. Poly(N-acryl amino acids): a new class of biologically active polyanions. J. Med. Chem. 43, 2591–2600 (2000).

    Article  CAS  Google Scholar 

  45. Naggi, A. et al. Toward a biotechnological heparin through combined chemical and enzymatic modification of the Escherichia coli K5 polysaccharide. Semin. Thromb. Hemost. 27, 437–443 (2001).

    Article  CAS  Google Scholar 

  46. Belting, M. et al. Tumor attenuation by combined heparan sulfate and polyamine depletion. Proc. Natl Acad. Sci. USA 99, 371–376 (2002).

    Article  CAS  Google Scholar 

  47. Merry, C. L., Lyon, M., Deakin, J. A., Hopwood, J. J. & Gallagher, J. T. Highly sensitive sequencing of the sulfated domains of heparan sulfate. J. Biol. Chem. 274, 18455–18462 (1999).

    Article  CAS  Google Scholar 

  48. Turnbull, J. E., Hopwood, J. J. & Gallagher, J. T. A strategy for rapid sequencing of heparan sulfate and heparin saccharides. Proc. Natl Acad. Sci. USA 96, 2698–2703 (1999).

    Article  CAS  Google Scholar 

  49. Vives, R. R. et al. Sequence analysis of heparan sulphate and heparin oligosaccharides. Biochem. J. 339, 767–773 (1999).

    Article  CAS  Google Scholar 

  50. Venkataraman, G., Shriver, Z., Raman, R. & Sasisekharan, R. Sequencing complex polysaccharides. Science 286, 537–542 (1999).

    Article  CAS  Google Scholar 

  51. Keiser, N., Venkataraman, G., Shriver, Z. & Sasisekharan, R. Direct isolation and sequencing of specific protein-binding glycosaminoglycans. Nature Med. 7, 123–128 (2001).

    Article  CAS  Google Scholar 

  52. Borsig, L. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Natl Acad. Sci. USA 98, 3352–3357 (2001).Anecdotal evidence has indicated that pharmacological doses of low-molecular-weight heparins serve a protective role against metastasis. This paper proposes that heparins interfere with the selectin-mediated interaction of cancer cells with their stroma.

    Article  CAS  Google Scholar 

  53. Petitou, M. et al. Experimental proof for the structure of a thrombin-inhibiting heparin molecule. Chemistry 7, 858–873 (2001).

    Article  CAS  Google Scholar 

  54. Ho, G., Broze, G. J. Jr & Schwartz, A. L. Role of heparan sulfate proteoglycans in the uptake and degradation of tissue factor pathway inhibitor-coagulation factor Xa complexes. J. Biol. Chem. 272, 16838–16844 (1997).

    Article  CAS  Google Scholar 

  55. Nugent, M. A. & Iozzo, R. V. Fibroblast growth factor-2. Int. J. Biochem. Cell Biol. 32, 115–120 (2000).

    Article  CAS  Google Scholar 

  56. Derksen, P. W. et al. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 99, 1405–1410 (2002).

    Article  CAS  Google Scholar 

  57. Lin, X. & Perrimon, N. Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling. Nature 400, 281–284 (1999).

    Article  CAS  Google Scholar 

  58. Tsuda, M. et al. The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. Nature 400, 276–280 (1999).

    Article  CAS  Google Scholar 

  59. Ma, Y. Q. & Geng, J. G. Heparan sulfate-like proteoglycans mediate adhesion of human malignant melanoma A375 cells to P-selectin under flow. J. Immunol. 165, 558–565 (2000).

    Article  CAS  Google Scholar 

  60. Hoffman, M. P. et al. Cell type-specific differences in glycosaminoglycans modulate the biological activity of a heparin-binding peptide (RKRLQVQLSIRT) from the G domain of the laminin-α1 chain. J. Biol. Chem. 276, 22077–22085 (2001).

    Article  CAS  Google Scholar 

  61. Utani, A. et al. A unique sequence of the laminin-α 3G domain binds to heparin and promotes cell adhesion through syndecan-2 and -4. J. Biol. Chem. 276, 28779–28788 (2001).

    Article  CAS  Google Scholar 

  62. Lundmark, K. et al. Perlecan inhibits smooth muscle cell adhesion to fibronectin: role of heparan sulfate. J. Cell Physiol. 188, 67–74 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to acknowledge financial assistance from the Burroughs Wellcome Foundation, the Arnold and Mabel Beckman Foundation, the CapCure Foundation and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Ram Sasisekharan, Zachary Shriver & Ganesh Venkataraman

  2. Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Ram Sasisekharan

  3. Division of Hematology and Oncology, New England Medical Center, Tufts University School of Medicine, Boston, 02111, Massachusetts, USA

    Uma Narayanasami

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  1. Ram Sasisekharan
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Correspondence to Ram Sasisekharan.

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DATABASES

Cancer.gov

breast cancer

colon cancer

colorectal cancer

mesotheliomas

multiple myeloma

ovarian cancer

pancreatic cancer

uterine carcinoma

LocusLink

bone morphogenetic proteins

collagen

endostatin

FGF1

FGF2

glypican-1

GPC3

heparanases

hepatocyte growth factor

insulin-like growth factor-2

interleukin-8

laminin

platelet-derived growth factor

P-selectin

Sonic hedgehog

syndecan-1

transforming growth factor-β

VEGF

WNT

OMIM

Simpson–Golabi–Behmel syndrome

FURTHER INFORMATION

Consortium for Functional Glycomics

Glycoforum home page

Glossary

PROTEOGLYCAN

A glycoprotein that consists of a core protein sequence and glycosaminoglycan extensions. Proteoglycans that contain heparan-sulphate glycosaminoglycan side chains are called heparan-sulphate proteoglycans.

SYNDECAN

A membrane-bound proteoglycan that contains a large extracellular domain with attached heparan-sulphate glycosaminoglycan chains, a conserved transmembrane domain and a small cytoplasmic domain.

GLYPICAN

A heparan-sulphate proteoglycan that is tethered to the membrane by a glycosylphosphatidylinositol anchor. The core protein contains a conserved cysteine-rich globular region and several glycosaminoglycan attachment sites.

PERLECAN

A proteoglycan that is typically extruded into the extracellular space.

HEPARIN

A highly sulphated member of the heparan-sulphate glycosaminoglycan family. Typically present in mast cells, where it acts as a storage depot for proteases, heparin is used pharmacologically as an anticoagulant.

PROPERTY-ENCODED NOMENCLATURE

(PEN). A rational system for defining a polymer that is based on the properties of its monomeric units. This system forms the basis for a computationally aided sequencing approach for heparan-sulphate glycosaminoglycan complex oligosaccharides.

ANTITHROMBIN III

(AT-III). An inhibitor of the coagulation cascade, specifically Factor Xa and Factor IIa (thrombin). Binding of AT-III to a specific pentasaccharide sequence in heparan sulphate results in a conformational change in AT-III, increasing its anticoagulant activity by orders of magnitude. Factor Xa is a serine protease of the coagulation cascade. Factor Xa activates thrombin — the penultimate step of the coagulation cascade.

MACROGLOSSIA

Tongue enlargement, leading to functional and cosmetic problems.

MACROSOMIA

Atypically large body size.

SULPHATION PATTERN

Each HSGAG disaccharide unit can be differentially sulphated at four possible positions. On the uronic acid, the 2-O position might be sulphated or unsulphated. For the glucosamine, the 6-O and 3-O positions might also be sulphated or unsulphated. Finally, the N-position of the glucosamine can be N-sulphated, acetylated or unsubstituted.

LOW-MOLECULAR-WEIGHT HEPARIN

(LMWH). Developed to maintain the potent anticoagulant affect of heparin but to reduce the number of side effects. LMWHs are generated by enzymatic or chemical means.

THROMBIN

Also known as Factor IIa, it is the penultimate factor of the coagulation cascade. Thrombin converts fibrinogen into fibrin, which is ultimately responsible for clot formation.

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Sasisekharan, R., Shriver, Z., Venkataraman, G. et al. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat Rev Cancer 2, 521–528 (2002). https://doi.org/10.1038/nrc842

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