Fux Liat, Ilan Neta, Sanderson Ralph D, Vlodavsky Israel
Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, P. O. Box 9649, Haifa 31096, Israel.
Trends Biochem Sci. 2009 Oct;34(10):511-9. doi: 10.1016/j.tibs.2009.06.005. Epub 2009 Sep 3.
Heparanase activity is strongly implicated in structural remodeling of the extracellular matrix, a process which can lead to invasion by tumor cells. In addition, heparanase augments signaling cascades leading to enhanced phosphorylation of selected protein kinases and increased gene transcription associated with aggressive tumor progression. This function is apparently independent of heparan sulfate and enzyme activity, and is mediated by a novel protein domain localized at the heparanase C-terminus. Moreover, the functional repertoire of heparanase is expanded by its regulation of syndecan clustering, shedding, and mitogen binding. Recent reports indicate that modified glycol-split heparin, which inhibits heparanase activity, can profoundly inhibit the progression of tumor xenografts produced by myeloma and carcinoma cells, thus moving anti-heparanase therapy closer to reality.
乙酰肝素酶活性与细胞外基质的结构重塑密切相关，这一过程可能导致肿瘤细胞的侵袭。此外，乙酰肝素酶增强信号级联反应，导致特定蛋白激酶的磷酸化增强以及与侵袭性肿瘤进展相关的基因转录增加。该功能显然独立于硫酸乙酰肝素和酶活性，由位于乙酰肝素酶C末端的一个新的蛋白结构域介导。此外，乙酰肝素酶对syndecan聚集、脱落和丝裂原结合的调节扩展了其功能范围。最近的报告表明，抑制乙酰肝素酶活性的修饰糖解肝素可显著抑制骨髓瘤和癌细胞产生的肿瘤异种移植物的进展，从而使抗乙酰肝素酶治疗更接近现实。
