Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model
Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model
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DOI：
10.1158/0008-5472.can-05-1560
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发表时间：
2005-10-15
期刊：
影响因子：
11.2
通讯作者：
Gladson, CL
中科院分区：
文献类型：
--
作者：
Fears, CY;Grammer, JR;Gladson, CL
宿主抗血管生成因子抵抗肿瘤生长。基质细胞蛋白，血小板反应蛋白-2（TSP-2），已被证明在致癌物诱导的皮肤癌模型中作为抗血管生成因子。在这里，使用体内恶性胶质瘤模型，其中评估脑内植入GL 261小鼠胶质瘤细胞后形成的肿瘤的特征，我们发现在TSP-2（-/-）小鼠中增殖的肿瘤中肿瘤生长和微血管密度显著增强。从机制上讲，基质金属蛋白酶（MMP）-2与新血管生成相关，并且已经提出，可利用的MMP-2的水平可以通过与TSP-2形成复合物而下调，TSP-2被低密度脂蛋白受体相关蛋白1（LRP 1）内化。我们发现MMP-2和MMP-9在TSP-2（-/-）小鼠中增殖的肿瘤中表达升高，优先定位于微血管。在野生型小鼠中，MMP-2与TSP-2在肿瘤微血管中共表达。在体外，除了重组（rec）TSP-2的小鼠脑微血管内皮细胞MMP-2水平和入侵的机制，可以抑制竞争性抑制剂的配体结合LRP 1或siLRP 1。因此，TSP-2的抗血管生成活性能够部分地通过降低肿瘤微血管系统中MMP-2的水平来抑制神经胶质瘤的生长。这种机制是由LRP 1介导的。
Host antiangiogenesis factors defend against tumor growth. The matricellular protein, thrombospondin-2 (TSP-2), has been shown to act as an antiangiogenesis factor in a carcinogen-induced model of skin cancer. Here, using an in vivo malignant glioma model in which the characteristics of the tumors formed after intracerebral implantation of GL261 mouse glioma cells are assessed, we found that tumor growth and microvessel density were significantly enhanced in tumors propagated in TSP-2(-/-) mice. Mechanistically, matrix metalloproteinase (MMP)-2 has been associated with neoangiogenesis and it has been proposed that the levels of available MMP-2 may be down-regulated by formation of a complex with TSP-2 that is internalized by low-density lipoprotein receptor-related protein 1 (LRP1). We found elevated expression of MMP-2 and MMP-9 in tumors propagated in TSP-2(-/-) mice, with a preferential localization in the microvasculature. In wild-type mice, MMP-2 was coexpressed with TSP-2 in the tumor microvasculature. In vitro, addition of recombinant (rec) TSP-2 to mouse brain microvessel endothelial cells reduced MMP-2 levels and invasion through mechanisms that could be inhibited by a competitive inhibitor of ligand binding to LRP1 or by siLRP1. Thus, the antiangiogenic activity of TSP-2 is capable of inhibiting the growth of gliomas in part by reducing the levels of MMP-2 in the tumor microvasculature. This mechanism is mediated by LRP1.