Heparanase as mediator of angiogenesis: mode of action

被引:275
作者
Elkin, M
Ilan, N
Ishai-Michaeli, R
Friedmann, Y
Papo, O
Pecker, I
Vlodavsky, I
机构
[1] Hadassah Hebrew Univ Hosp, Dept Oncol, IL-91120 Jerusalem, Israel
[2] Hadassah Hebrew Univ Hosp, Dept Pathol, IL-91120 Jerusalem, Israel
[3] InSight, IL-76121 Rehovot, Israel
关键词
heparan sulfate proteoglycans; extracellular matrix; endothelial cells; basic fibroblast growth factor; wound healing;
D O I
10.1096/fj.00-0895fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Extracellular matrix (ECM) and basement membranes (BMs) present a physical barrier that requires enzymatic degradation during endothelial cell (EC) sprouting at early stages of angiogenesis. These multimolecular structures also serve as a storage depot for heparin-binding angiogenic factors. Heparan sulfate proteoglycans (HSPGs) are responsible for the self-assembly and integrity of the ECM and BM structure, as well as for sequestration of growth and differentiation factors. Recently, we reported the cloning of heparanase, an endo-beta-D-glucuronidase degrading heparan sulfate (HS), and provided direct evidence for its role in tumor metastasis. We now demonstrate that heparanase is intimately involved in angiogenesis and elucidate its mode of action. Apart from its direct involvement in ECM degradation and EC migration (vascular sprouting), heparanase releases active basic fibroblast growth factor (bFGF) from the subendothelial ECM, as well as bFGF-stimulating HS degradation fragments from the EC surface. Interestingly, ECM-derived HS fragments induced little or no potentiation of the growth-promoting activity of bFGF. The angiogenic effect of heparanase was demonstrated in vivo (via the Matrigel plug assay) by showing a three- to fourfold increase in neovascularization induced by murine T-lymphoma cells after stable transfection with the heparanase gene. Increased tissue vascularity was also observed in a mouse wound-healing model in response to topical administration of recombinant heparanase. Immunohistochemical staining of human colon carcinoma tissue revealed a high expression of the heparanase protein in the endothelium of sprouting capillaries and small vessels, but not of mature quiescent blood vessels. The ability of heparanase to promote tumor angiogenesis and its involvement in tumor metastasis make it a promising target for cancer therapy.
引用
收藏
页码:1661 / +
页数:16
相关论文
共 34 条
  • [11] Purification and characterization of placental heparanase and its expression by cultured cytotrophoblasts
    Goshen, Ran
    Hochberg, Abraham A.
    Korner, Gil
    Levy, Ehud
    Ishai-Michaeli, Rivka
    Elkin, Michael
    de Groot, Nathan
    Vlodaysky, Israel
    [J]. MOLECULAR HUMAN REPRODUCTION, 1996, 2 (09) : 679 - 684
  • [12] Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis
    Hulett, MD
    Freeman, C
    Hamdorf, BJ
    Baker, RT
    Harris, MJ
    Parish, CR
    [J]. NATURE MEDICINE, 1999, 5 (07) : 803 - 809
  • [13] Ilan N, 1999, J CELL SCI, V112, P3005
  • [14] Proteoglycans of the extracellular environment: Clues from the gene and protein side offer novel perspectives in molecular diversity and function
    Iozzo, RV
    Murdoch, AD
    [J]. FASEB JOURNAL, 1996, 10 (05) : 598 - 614
  • [15] IMPORTANCE OF SIZE AND SULFATION OF HEPARIN IN RELEASE OF BASIC FIBROBLAST GROWTH-FACTOR FROM THE VASCULAR ENDOTHELIUM AND EXTRACELLULAR-MATRIX
    ISHAIMICHAELI, R
    SVAHN, CM
    WEBER, M
    CHAJEKSHAUL, T
    KORNER, G
    EKRE, HP
    VLODAVSKY, I
    [J]. BIOCHEMISTRY, 1992, 31 (07) : 2080 - 2088
  • [16] Cloning and functional expression of a human heparanase gene
    Kussie, PH
    Hulmes, JD
    Ludwig, DL
    Patel, S
    Navarro, EC
    Seddon, AP
    Giorgio, NA
    Bohlen, P
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 261 (01) : 183 - 187
  • [17] Modulation of fibroblast growth factor-2 receptor binding, dimerization, signaling, and angiogenic activity by a synthetic heparin-mimicking polyanionic compound
    Miao, HQ
    Ornitz, DM
    Aingorn, E
    BenSasson, SA
    Vlodavsky, I
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (07) : 1565 - 1575
  • [18] HEPARANASES AND TUMOR-METASTASIS
    NAKAJIMA, M
    IRIMURA, T
    NICOLSON, GL
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 1988, 36 (02) : 157 - 167
  • [19] HEPARIN IS REQUIRED FOR CELL-FREE BINDING OF BASIC FIBROBLAST GROWTH-FACTOR TO A SOLUBLE RECEPTOR AND FOR MITOGENESIS IN WHOLE CELLS
    ORNITZ, DM
    YAYON, A
    FLANAGAN, JG
    SVAHN, CM
    LEVI, E
    LEDER, P
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1992, 12 (01) : 240 - 247
  • [20] Parish CR, 1999, CANCER RES, V59, P3433