Species-specific urokinase receptor ligands reduce glioma growth and increase survival primarily by an antiangiogenesis mechanism
Species-specific urokinase receptor ligands reduce glioma growth and increase survival primarily by an antiangiogenesis mechanism
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DOI：
10.1038/labinvest.3700089
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发表时间：
2004-06-01
影响因子：
5
通讯作者：
Laug, WE
中科院分区：
文献类型：
--
作者：
Bu, XY;Khankaldyyan, V;Laug, WE
通过位点特异性诱变和氨基末端聚乙二醇化产生具有改善的药代动力学的物种特异性尿激酶受体（uPAR）配体。这些分子被用于探测uPAR在脑肿瘤进展和血管生成中的作用。配体以种属特异性方式阻断基质胶中内皮细胞管的形成，并减少玻连蛋白梯度上基线和uPA氨基末端片段刺激的细胞迁移。用单一物种特异性或组合uPAR配体原位植入小鼠中的U87 MG胶质瘤的治疗导致肿瘤大小显著减小，这转化为存活时间的增加，并且当包括鼠特异性配体时最为显著。对肿瘤的进一步分析表明，减小的尺寸与肿瘤细胞增殖和平均血管密度的降低以及肿瘤细胞凋亡的增加相关。此外，在处理组中观察到胶原沉积的大幅增加。统计学分析显示，与单独药剂治疗相比，联合治疗显示出明显的协同作用。这些结果表明uPAR系统在脑肿瘤进展中的主要作用是在间质区室中，特别是在新血管形成中，这是侵袭性脑肿瘤的标志。
Species-specific urokinase receptor (uPAR) ligands with improved pharmacokinetics were generated by site-specific mutagenesis and amino-terminal pegylation. These molecules were used to probe the role of uPAR in brain tumor progression and angiogenesis. The ligands blocked endothelial cell tube formation in Matrigel in a species-specific manner and reduced both baseline and uPA amino-terminal fragment-stimulated cell migration on vitronectin gradients. Treatment of U87MG gliomas implanted orthotopically in mice with single species-specific or combination uPAR ligands resulted in significant decreases in tumor size, which translated to increases in survival time, and which were most significant when the murine-specific ligand was included. Further analysis of tumors showed that the reduced sizes were correlated with a decrease in tumor cell proliferation and mean vessel density and an increase in tumor cell apoptosis. In addition, a large increase in collagen deposition was observed in the treated groups. Statistical analysis showed that the combination therapy demonstrated a clear synergy as compared to the individual agent treatments. These results suggest that the major role of the uPAR system in brain tumor progression is in the stromal compartment and particularly in neovascularization, a hallmark of invasive brain tumors.