Molecular properties and involvement of heparanase in cancer progression and normal development.
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 approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 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.
Vlodavsky
I
I
Department of Oncologyy, Hadassah-Hebrew University Hospital, POB 12000, Jerusalem 91120, Israel. vlodavsk@cc.huji.ac.il
Goldshmidt
O
O
Zcharia
E
E
Metzger
S
S
Chajek-Shaul
T
T
Atzmon
R
R
Guatta-Rangini
Z
Z
Friedmann
Y
Y
D000818:Animals; D002240:Carbohydrate Sequence; D018450:Disease Progression; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000503:physiopathology*; D009389:Neovascularization, Pathologic; D000099175:Heparanase
D005966:Glucuronidase; D000099175:Heparanase