Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development
Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development
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DOI：
10.1006/scbi.2001.0420
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发表时间：
2002-04-01
影响因子：
14.5
通讯作者：
Friedmann, Y
中科院分区：
文献类型：
--
作者：
Vlodavsky, I;Goldshmidt, O;Friedmann, Y
硫酸乙酰肝素蛋白聚糖（HSPG）的切割影响组织的完整性和功能状态，从而影响涉及细胞迁移和对细胞外微环境变化的响应的基本正常和病理现象。乙酰肝素酶在特定的链内位点降解硫酸乙酰肝素（HS），合成为一种类似于65 kDa的潜在蛋白，其在N-末端被加工成类似于50 kDa的高活性形式。乙酰肝素酶优先在人类肿瘤中表达，并且其在低转移性肿瘤细胞中的过度表达在实验动物中赋予高度侵袭性表型。乙酰肝素酶还从肿瘤微环境中释放血管生成因子和HS的辅助片段，并在体内诱导血管生成反应。因此，乙酰肝素酶可以促进肿瘤细胞的侵袭、血管形成和在均匀的微环境中存活，这些都是癌症进展中的关键事件。这些观察结果，乙酰肝素酶抑制分子的抗癌作用，以及一个单一的主要功能乙酰肝素酶的意外鉴定表明，该酶是一个有前途的药物开发的目标。
Cleavage of heparan sulphate proteoglycans (HSPGs) 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. Heparanase, degrading heparan sulphate (HS) at specific intrachain sites, is synthesized as a latent similar to65 kDa protein that is processed at the N-terminus into a highly active similar to50 kDa form. The heparanase enzyme is preferentially expressed in human tumours and its overexpression in low-metastatic tumour cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumour microenvironment and induces an angiogenic response in vivo. Heparanase may thus facilitate tumour cell invasion, vascularization and survival in a even microenvironment, all critical events in cancer progression. These observations, the anticancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development.