Inhibition of tumor metastasis by heparanase inhibiting species of heparin.
Inhibition of tumor metastasis by heparanase inhibiting species of heparin.
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通过抑制肝素酶的种类的肝素来抑制肿瘤转移。
DOI：
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发表时间：
1994
期刊：
影响因子：
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通讯作者：
T. Peretz
中科院分区：
文献类型：
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作者：
Israel Vlodavsky;M. Mohsen;O. Lider;Svahn Cm;Ekre Hp;M. Vigoda;R. Ishai‐Michaeli;T. Peretz
乙酰肝素酶活性与淋巴瘤、黑色素瘤和乳腺癌细胞系的转移潜能相关。我们研究了各种修饰的肝素和来自解聚肝素的大小均匀的寡糖抑制（1）天然产生的内皮下细胞外基质（ECM）中硫酸乙酰肝素的乙酰肝素酶介导的降解和（2）C57 BL小鼠B16-BL 6黑色素瘤细胞的肺定植的能力。肝素酶的抑制最好通过含有16个或更多个糖单元并且在N和O位置都具有硫酸酯基团的肝素物质来实现。低硫酸寡糖是有效的乙酰肝素酶抑制剂比中等和高硫酸级分的相同大小的糖。虽然O-硫酸化消除了肝素的乙酰肝素酶抑制作用，但O-硫酸化、N-取代（例如N-乙酰基或N-己酰基）的肝素种类保留了高抑制活性。乙酰肝素酶活性的有效抑制剂也是肿瘤侵袭和肺定植的有效抑制剂。肝素组分与高，低抗凝活性表达相似的高抗乙酰肝素酶和抗转移活性。肝素抑制黑色素瘤细胞乙酰肝素酶和肺定殖的结构要求与（1）ECM结合碱性成纤维细胞生长因子（b-FGF）释放和（2）刺激b-FGF受体结合和促有丝分裂活性的结构要求不同。这些结果表明，肝素和其他聚阴离子分子的大小，硫酸化和取代基团不同的各种nonantibiotics物种可以被设计为引起特定的影响，导致在肿瘤转移和自身免疫，或刺激新血管形成和伤口愈合的细胞侵袭的抑制。
Heparanase activity correlates with the metastatic potential of lymphoma, melanoma and mammary adenocarcinoma cell lines. We investigated the ability of various modified species of heparin and size-homogeneous oligosaccharides derived from depolymerized heparin to inhibit (1) heparanase-mediated degradation of heparan sulfate in a naturally produced subendothelial extracellular matrix (ECM), and (2) lung colonization of B16-BL6 melanoma cells in C57BL mice. Inhibition of heparanase was best achieved by heparin species containing 16 or more sugar units and having sulfate groups at both the N and O positions. Low-sulfate oligosaccharides were less effective heparanase inhibitors than medium- and high-sulfate fractions of the same-size saccharide. While O-desulfation abolished the heparanase-inhibiting effect of heparin, O-sulfated, N-substituted (e.g. N-acetyl or N-hexanoyl) species of heparin retained high inhibitory activity. Potent inhibitors of heparanase activity were also efficient inhibitors of tumor invasion and lung colonization. Heparin fractions with high and low anticoagulant activity expressed similar high antiheparanase and antimetastatic activities. Structural requirement for the inhibition of melanoma cell heparanase and lung colonization by species of heparin were different from those identified for (1) release of ECM-bound basic fibroblast growth factor (b-FGF) and (2) stimulation of b-FGF receptor binding and mitogenic activity. These results indicate that various nonanticoagulant species of heparin and other polyanionic molecules differing in size, sulfation and substituted groups can be designed to elicit specific effects resulting in the inhibition of cell invasion in tumor metastasis and autoimmunity, or stimulation of neovascularization and wound healing.