Molecular properties and involvement of heparanase in cancer progression and normal development

被引:66
作者
Vlodavsky, I
Goldshmidt, O
Zcharia, E
Metzger, S
Chajek-Shaul, T
Atzmon, R
Guatta-Rangini, Z
Friedmann, Y
机构
[1] Hadassah Hebrew Univ Hosp, Dept Oncol, IL-91120 Jerusalem, Israel
[2] Hadassah Hebrew Univ Hosp, Dept Med, IL-91120 Jerusalem, Israel
关键词
metastasis; angiogenesis; heparanase; endoglycosidase; heparan sulfate proteoglycans; extracellular matrix;
D O I
10.1016/S0300-9084(01)01318-9
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
Heparan sulfate proteoglycans (HSPGs) play a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Here, we describe the molecular properties, expression and function of a human heparanase, degrading HS at specific intrachain sites. The enzyme is synthesized as a latent similar to 65 kDa protein that is processed at the N-terminus into a highly active similar to 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and human tumor tissues. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also releases ECM-resident angiogenic factors in vitro and its overexpression induces an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity. The unexpected identification of a single predominant functional heparanase suggests that the enzyme is a promising target for drug development. In fact, treatment with heparanase inhibitors markedly reduces tumor growth, metastasis and autoimmune disorders in animal models. Studies are underway to elucidate the involvement of heparanase in normal processes such as implantation, embryonic development, morphogenesis, tissue repair, inflammation and HSPG turnover. Heparanase is the first functional mammalian HS-degrading enzyme that has been cloned, expressed and characterized. This may lead to identification and cloning of other glycosaminoglycan degrading enzymes, toward a better understanding of their involvement and significance in normal and pathological processes. (C) 2001 Societe francaise de biochimie et biologie moleculaire/Editions scientifiques et medicales Elsevier SAS. All rights reserved.
引用
收藏
页码:831 / 839
页数:9
相关论文
共 38 条
  • [1] Heparanases: endoglycosidases that degrade heparan sulfate proteoglycans
    Bame, KJ
    [J]. GLYCOBIOLOGY, 2001, 11 (06) : 91R - 98R
  • [2] 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
  • [3] 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
  • [4] Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis
    Borsig, L
    Wong, R
    Feramisco, J
    Nadeau, DR
    Varki, NM
    Varki, A
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (06) : 3352 - 3357
  • [5] Heparanase, a potential regulator of cell-matrix interactions
    Dempsey, LA
    Brunn, GJ
    Platt, JL
    [J]. TRENDS IN BIOCHEMICAL SCIENCES, 2000, 25 (08) : 349 - 351
  • [6] Genomic organization and chromosome localization of the newly identified human heparanase gene
    Dong, J
    Kukula, AK
    Toyoshima, M
    Nakajima, M
    [J]. GENE, 2000, 253 (02) : 171 - 178
  • [7] Heparanase as mediator of angiogenesis: mode of action
    Elkin, M
    Ilan, N
    Ishai-Michaeli, R
    Friedmann, Y
    Papo, O
    Pecker, I
    Vlodavsky, I
    [J]. FASEB JOURNAL, 2001, 15 (07) : 1661 - +
  • [8] Processing of the human heparanase precursor and evidence that the active enzyme is a heterodimer
    Fairbanks, MB
    Mildner, AM
    Leone, JW
    Cavey, GS
    Mathews, WR
    Drong, RF
    Slightom, JL
    Bienkowski, MJ
    Smith, CW
    Bannow, CA
    Heinrikson, RL
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (42) : 29587 - 29590
  • [9] FOLKMAN J, 1992, ADV EXP MED BIOL, V313, P355
  • [10] 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