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
  • [1] AIRBANKS MB, 1999, J BIOL CHEM, V274, P29587
  • [2] PERLECAN, BASAL LAMINA PROTEOGLYCAN, PROMOTES BASIC FIBROBLAST GROWTH FACTOR-RECEPTOR BINDING, MITOGENESIS, AND ANGIOGENESIS
    AVIEZER, D
    HECHT, D
    SAFRAN, M
    EISINGER, M
    DAVID, G
    YAYON, A
    [J]. CELL, 1994, 79 (06) : 1005 - 1013
  • [3] Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
    Bergers, G
    Brekken, R
    McMahon, G
    Vu, TH
    Itoh, T
    Tamaki, K
    Tanzawa, K
    Thorpe, P
    Itohara, S
    Werb, Z
    Hanahan, D
    [J]. NATURE CELL BIOLOGY, 2000, 2 (10) : 737 - 744
  • [4] Functions of cell surface heparan sulfate proteoglycans
    Bernfield, M
    Götte, M
    Park, PW
    Reizes, O
    Fitzgerald, ML
    Lincecum, J
    Zako, M
    [J]. ANNUAL REVIEW OF BIOCHEMISTRY, 1999, 68 : 729 - 777
  • [5] Differential ability of heparan sulfate proteoglycans to assemble the fibroblast growth factor receptor complex in situ
    Chang, Z
    Meyer, K
    Rapraeger, AC
    Friedl, A
    [J]. FASEB JOURNAL, 2000, 14 (01) : 137 - 144
  • [6] Heparanase, a potential regulator of cell-matrix interactions
    Dempsey, LA
    Brunn, GJ
    Platt, JL
    [J]. TRENDS IN BIOCHEMICAL SCIENCES, 2000, 25 (08) : 349 - 351
  • [7] Blood vessel formation: What is its molecular basis?
    Folkman, J
    DAmore, PA
    [J]. CELL, 1996, 87 (07) : 1153 - 1155
  • [8] Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma -: Evidence for its role in colonic tumorigenesis
    Friedmann, Y
    Vlodavsky, I
    Aingorn, H
    Aviv, A
    Peretz, T
    Pecker, I
    Pappo, O
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2000, 157 (04) : 1167 - 1175
  • [9] 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
    GILAT, D
    HERSHKOVIZ, R
    GOLDKORN, I
    CAHALON, L
    KORNER, G
    VLODAVSKY, I
    LIDER, O
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (05) : 1929 - 1934
  • [10] HEPARANASE ACTIVITY IN CULTURED ENDOTHELIAL-CELLS
    GODDER, K
    VLODAVSKY, I
    ELDOR, A
    WEKSLER, BB
    HAIMOVITZFREIDMAN, A
    FUKS, Z
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 1991, 148 (02) : 274 - 280