Advertisement

Cancer and Metastasis Reviews

, Volume 15, Issue 2, pp 177–186 | Cite as

Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor

  • Israel Vlodavsky
  • Hua-Quan Miao
  • Benjamin Medalion
  • Pamela Danagher
  • Dina Ron
Tumor Angiogenesis

Abstract

Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues [1,2]. The basic HSPG structure consists of a protein core to which several linear heparan sulfate (HS) chains are covalently attached. The polysaccharide chains are typically composed of repeating hexuronic and D-glucosamine disaccharide units that are substituted to a varying extent with N- and O-linked sulfate moieties and N-linked acetyl groups [1,2]. Beside serving as a scaffold for the attachment of various ECM components (e.g., collagen, laminin, fibronectin), the binding of HS to certain proteins has been suggested to induce a conformational change which may lead to the exposure of novel reactive determinants or conversely stabilize an innert protein configuration [1–4]. Of particular significance is the interaction of HS with fibroblast growth factors (FGFs), mediating their sequestration, stabilization and high affinity receptor binding and signaling [3–7]. Cellular responses to FGFs may hence be modulated by metabolic inhibitors of HS synthesis and sulfation, HS-degrading enzymes, and synthetic mimetics of heparin/HS. In the present review we focus on the involvement of HS in basic FGF (bFGF) receptor binding and mitogenic activity and its modulation by species of heparin, HS, and synthetic polyanionic ‘heparin-mimicking’ compounds. The results are discussed in relation to the current thoughts on the dual involvement of low and high affinity receptor sites in the growth promoting and angiogenic activities of bFGF and other heparin-binding growth factors.

Key words

heparin-mimicking compounds extracellular matrix heparan sulfate degrading enzymes FGF-receptor binding 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kjellen L, Lindahl U: Proteoglycans: structures and interactions. Ann Rev Biochem 60: 443–475, 1991Google Scholar
  2. 2.
    Jackson RL, Busch SJ, Cardin AD: Glycosaminoglycans: molecular properties, protein interactions and role in physiological processes. Physiol Rev 71: 481–539, 1991Google Scholar
  3. 3.
    Ruoslahti E, Yamaguchi Y: Proteoglycans as modulators of growth factor activities. Cell 64: 867–869, 1991Google Scholar
  4. 4.
    Vlodavsky I, Bar-Shavit R, Korner G, Fuks Z: Extracellular matrix-bound growth factors, enzymes and plasma proteins. In: Rohrbach DH, Timple R (eds) Basement Membranes: Cellular and Molecular Aspects. Academic Press Inc., Orlando, Fl, 1993, pp 327–343Google Scholar
  5. 5.
    Folkman J, Klagsbrun M: Angiogenic factors. Science 235: 442–447, 1987Google Scholar
  6. 6.
    Saksela O, Moscatelli D, Sommer A, Rifkin DB: Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol 107: 743–751, 1988Google Scholar
  7. 7.
    Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM: Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64: 841–848, 1991Google Scholar
  8. 8.
    Folkman J, Shing Y: Control of angiogenesis by heparin and other sulfated polysaccharides. Adv Exp Med Biol 313: 355–364, 1992Google Scholar
  9. 9.
    Azizkhan R, Azizkhan J, Zetter B, Folkman J: Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med 152: 931–944, 1980Google Scholar
  10. 10.
    Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M: Heparin-affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223: 1296–1298, 1984Google Scholar
  11. 11.
    Folkman J, Shing Y: Angiogenesis. J Biol Chem 267: 10931–10934, 1992Google Scholar
  12. 12.
    Thornton SC, Mueller SN, Levine EM: Human endothelial cells: use of heparin in cloning and long term serial cultivation. Science 222: 623–625, 1983Google Scholar
  13. 13.
    Gospodarowicz D, Cheng J: Heparin protects basic and acidic FGF from inactivation. J Cell Physiol 128: 475–484, 1986Google Scholar
  14. 14.
    Rapraeger A: In the clutches of proteoglycans: how does heparan sulfate regulate FGF binding. Curr Biol 2: 645–649, 1995Google Scholar
  15. 15.
    Vlodavsky I, Folkman J, Sullivan R, Fridman R, Ishai-Michaelli R, Sasse J, Klagsbrun M: Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Natl Acad Sci USA 84: 2292–2296, 1987Google Scholar
  16. 16.
    Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I: A heparin-binding angiogenic protein-basic fibroblast growth factor-is stored within basement membrane. Am J Pathol 130: 393–400, 1980Google Scholar
  17. 17.
    Fedarko N, Conrad E: A unique heparin sulfate in the nuclei of hepatocytes: structural changes with the growth state of the cells. J Cell Biol 102: 587–599, 1986Google Scholar
  18. 18.
    Crum R, Szabo S, Folkman J: A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 230: 1375–1378, 1985Google Scholar
  19. 19.
    Cardon-Cardo C, Vlodavsky I, Haimovitz-Friedman A, Hicklin D, Fuks Z: Expression of basic fibroblast growth factor in normal human tissues. Lab Invest 63: 832–840, 1990Google Scholar
  20. 20.
    Gonzalez AM, Buscaglia M, Ong M, Baird A: Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol 110: 753–765, 1990Google Scholar
  21. 21.
    Bashkin P, Doctrow S, Klagsbrun M, Svahn CM, Folkman J, Vlodavsky I: Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry 28: 1737–1743, 1989Google Scholar
  22. 22.
    Hanneken A, Maher PA, Baird A: Hig affinity immunoreactive FGF receptors in the extracellular matrix of vascular endothelial cells-implications for the modulation of FGF-2. J Cell Biol 128: 1221–1228, 1995Google Scholar
  23. 23.
    Vlodavsky I, Bar-Shavit R, Ishai-Michaeli R, Bashkin P, Fukz Z: Extracellular sequestration and release of fibroblast growth factor: a regulatory mechanism? Trends Biochern Sci 16: 268–271, 1991Google Scholar
  24. 24.
    Ishai-Michaeli R, Svaln C-M, Chajek-Shaul T, Korner G, Ekre H-P, Vlodavsky I: Importance of size and sulfation of heparin in release of basic fibroblast factor from the vascular endothelium and extracellular matrix. Biochemistry 31: 2080–2088, 1992Google Scholar
  25. 25.
    Miao H-Q, Ishai-Michaeli R, Atzmon R, Peretz T, Vlodavsky I: Sulfate moieties in the subendothelial extracellular matrix are involved in bFGF sequestration, dimerization and stimulation of cell proliferation. J Biol Chem 271: 4879–4886, 1996Google Scholar
  26. 26.
    Brunner G, Gabrilove J, Rifkin DB, Wilson EL: Phospholipase C release of basic fibroblast growth factor from human bone marrow cultures as a biologically active complex with a phosphatidylinositol-anchored heparan sulfate proteoglycan. J Cell Biol 114: 1275–1283, 1991Google Scholar
  27. 27.
    Bashkin P, Neufeld G, Gitay GH, Vlodavsky I: Release of cell surface-associated basic fibroblast growth factor by glycosylphosphatidylinositol-specific phospholipase C. J Cell Physiol 151:126–137, 1992Google Scholar
  28. 28.
    Thompson RW, Whales GF, Saunders KB Hores T, D'Amore P: Heparin-mediated release of fibroblast growth factor-like activity into the circulation of rabbits. Growth Factors 3:221–229, 1990Google Scholar
  29. 29.
    Ishai-Michaeli R, Eldor A, Vlodavsky I: Heparanase activity expressed by platelets, neutrophils and lymphoma cells releases active fibroblast growth factor from extracellular matrix. Cell Reg 1:833–842, 1990Google Scholar
  30. 30.
    Benezra M, Vlodavsky I, Ishai MR, Neufeld G, Bar-Shavit R: Thrombin-induced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix. Blood 81:3324–3331, 1993Google Scholar
  31. 31.
    Saksela O, Rifkin DB: Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110:767–775, 1990Google Scholar
  32. 32.
    Roberts R, Gallagher J, Spooncer S, Allen TD, Bloomfield F, Dexter TM: Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature 332:376–378, 1988Google Scholar
  33. 33.
    Tanaka Y, Adams DH, Shaw S: Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes. Immunol Today 14:111–115, 1993Google Scholar
  34. 34.
    Hoogewerf AJ, Leone JW, Reardon M, Howe WJ, Asa D, Heinrikson RL, Ledbetter SR: CXC chemokines connective tissue activation peptide-III and neutrophil activating peptide-2 are heparin/heparan sulfate-degrading enzymes. J Biol Chem 270:3268–3277, 1995Google Scholar
  35. 35.
    Gilat D, Hershkoviz R, Goldkorn I, Cahalon L, Korner G, Vlodavsky I, Lider O: Molecular behavior adapts to context: heparanase functions as an extracellular matrix-degrading enzyme or as a T cell adhesion molecule, depending on the local pH. J Exp Med 181:1929–1934, 1995Google Scholar
  36. 36.
    Roghani M, Moscatelli D: Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms. J Biol Chem 267:22156–22162, 1992Google Scholar
  37. 37.
    Bernfield M, Hooper KC: Possible regulation of FGF activity by syndecan, an integral membrane heparan sulfate proteoglycan. Ann NY Acad Sci 638:182–194, 1991Google Scholar
  38. 38.
    Guimond S, Maccarana M, Olwin BB, Lindahl U, Rapraeger AC: Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4. J Biol Chem 268:23906–23914, 1993Google Scholar
  39. 39.
    Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P: Heparin is required for cell-free binding of bFGF to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol 12:240–247, 1992Google Scholar
  40. 40.
    Schlessinger J, Lax I, Lemmon M: Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 83:357–360, 1995Google Scholar
  41. 41.
    Miao H-Q, Fritz TA, Esko JD, Zimmermann J, Yayon A, Vlodavsky I: Heparan sulfate primed on beta-D-xylosides restores binding of basic fibroblast growth factor. J Cell Biochem 57:173–184, 1995Google Scholar
  42. 42.
    Roghani M, Mansukhani A, Dell'Era P, Bellosta P, Basilico C, Rifkin DB, Moscatelli D: Heparin increases the affinity of basic fibroblast growth factor for its receptor but is not required for binding. J Biol Chem 269:3976–3984, 1994Google Scholar
  43. 43.
    Caccia P, Cletini O, Isacchi A, Bergonozoni L, Orsini G: Biochemical characterization of the molecular interaction between recombinant basic fibroblast growth factor and a recombinant soluble fibroblast growth factor receptor. Biochem J 294:639–644, 1993Google Scholar
  44. 44.
    Pantoliano MW, Horlick RA, Springer BA, Van Dyke DE, Tobery T, Wetmore DR, Lear JD, Nahapetian AT, Bradley JD, Sisk WP: Multivalent ligand-receptor interactions in fibroblast growth factor system produce a cooperative growth factor and heparin mechanism for receptor dimerization. Biochemistry 33:10229–10248, 1994Google Scholar
  45. 45.
    Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J, Lax I: Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell 79:1015–1024, 1994Google Scholar
  46. 46.
    Moscatelli D: Basic fibroblast growth factor (bFGF) dissociates rapidly from heparan sulfates but slowly from receptors. Implications for mechanisms of bFGF release from pericellular matrix. J Biol Chem 267:25803–25809, 1992Google Scholar
  47. 47.
    Gitay-Goren H, Cohen T, Tessler S, Soker S, Gengrinovitch S, Rockwell P, Klagsbrun M, Levi B-Z, Neufeld G: Selective binding of VEGF121 to one of the three VEGF receptors of vascular endothelial cells. Biochem J 271:5519–5523, 1996Google Scholar
  48. 48.
    Kan M, Wang F Xu J, Crabb JW, Hon J, Mckeehan WL: An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 259:1918–1921, 1993Google Scholar
  49. 49.
    de Vos AM, Ultsch M, Kossiakoff AA: Human growth hormone and extracellular domain of its receptor; Crystal structure of the complex. Science 255:306–312, 1992Google Scholar
  50. 50.
    Sasisekharan R, Moses MA, Nugent MA, Cooney CL, Langer R: Heparinase inhibits neovascularization. Proc Natl Acad Sci USA 91:1524–1528, 1994Google Scholar
  51. 51.
    Reich-Slotky R, Shaoul E, Berman B, Graziani G, Ron D: Chimeric molecules between keratinocyte growth factor and basic fibroblast growth factor define domains that confer receptor binding specificities. J Biol Chem 270:29813–29818, 1995Google Scholar
  52. 52.
    Aviezer D, Levy E, Safran M, Svahn C, Buddecke E, Schmidt A, David G, Vlodavsky I, Yayon A: Differential structural requirements of heparin and heparan sulfate proteoglycans that promote binding of basic fibroblast growth factor to its receptor. J Biol Chem 269:114–121, 1994Google Scholar
  53. 53.
    Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A: Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 79:1005–1013, 1994Google Scholar
  54. 54.
    Reich-Slotky R, Bonneh-Barkay D, Shaoul E, Bluma B, Svahn CM, Ron D: Differential effect of cell-associated heparan sulfates on the binding of keratinocyte growth factor (KGF) and acidic fibroblast growth factor to the KGF receptor. J Biol Chem 269:32279–32285, 1994Google Scholar
  55. 55.
    Benezra M, Vlodavsky I, Yayon A, Bar-Shavit R, Regan J, Chang M, Ben SS: Reversal of basic fibroblast growth factor-mediated autocrine cell transformation by aromatic anionic compounds. Cancer Res 52:5656–5662, 1992Google Scholar
  56. 56.
    Benezra M, Ben-Sasson S, Regan J, Chang M, Bar-Shavit R, Vlodavsky I: Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyaromatic anionic compounds. Arterioscler Thromb 14: 1992–1999, 1994Google Scholar
  57. 57.
    Vlodavsky I, Miao HQ, Atzmon R, Levi E, Zimmermann J, Bar-Shavit R, Peretz T, Ben-Sasson S: Control of cell proliferation by heparan sulfate and heparin-binding growth factors. Thromb Haemost 74:534–540, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Israel Vlodavsky
    • 1
  • Hua-Quan Miao
    • 1
  • Benjamin Medalion
    • 1
  • Pamela Danagher
    • 2
  • Dina Ron
    • 3
  1. 1.Department of OncologyHadassah-Hebrew University HospitalJerusalemIsrael
  2. 2.IBEX TechnologiesMontrealCanada
  3. 3.Department of Biology, TechnionIsrael Institute of TechnologyHaifaIsrael

Personalised recommendations