De Boüard Sophie, Guillamo Jean-Sébastien, Christov Christo, Lefévre Nathalie, Brugières Pierre, Gola Eleonora, Devanz Pauline, Indraccolo Stefano, Peschanski Marc
INSERM U 421, Neuroplasticity and Therapeutics, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil, France.
Hum Gene Ther. 2003 Jun 10;14(9):883-95. doi: 10.1089/104303403765701178.
Inhibition of angiogenesis has been considered among the most promising approaches to treat highly vascularized solid tumors such as glioblastoma. In this study, we designed and validated a new in vitro assay system based on the implantation of tumor cells into organotypic brain slice cultures. We evaluated the effects of local production of three endogenous inhibitors of angiogenesis, angiostatin, endostatin, and interferon (IFN)-alpha(1), using stably transfected rat (9L) and human (GL15) glioblastoma cells on tumor vascularization and growth. Despite similar effectiveness of the three proteins in a classic in vitro endothelial cell migration assay, IFN-alpha(1) demonstrated the most potent antiangiogenic effect in organotypic brain slice cultures. In vivo, after intracerebral implantation of such genetically modified glioblastoma cells, IFN-alpha(1) caused a dramatic decrease in tumor volume revealed by magnetic resonance imaging and by postmortem histology. The mechanisms of this antitumor effect were most likely caused by the major antiangiogenic action of the cytokine, because IFN-alpha(1) expression provoked a pronounced decrease in blood vessel density, which was accompanied by extensive necrosis in the body mass of the tumors. The median survival time of rats implanted intracerebrally with IFN-alpha-expressing 9L cells tripled, and was still significantly increased when these constituted only 1% of transplanted tumor cells. A similar effect was seen when 50% of the transplanted cells were replaced by IFN-alpha-expressing bone marrow stromal cells. These data point to the local delivery of IFN-alpha(1) using cell vectors as a potent tool for the inhibition of tumor-induced angiogenesis.
抑制血管生成被认为是治疗高度血管化实体瘤（如胶质母细胞瘤）最有前景的方法之一。在本研究中，我们设计并验证了一种基于将肿瘤细胞植入器官型脑片培养物的新型体外检测系统。我们使用稳定转染的大鼠（9L）和人（GL15）胶质母细胞瘤细胞，评估了三种内源性血管生成抑制剂血管抑素、内皮抑素和干扰素（IFN）-α1的局部产生对肿瘤血管生成和生长的影响。尽管这三种蛋白在经典的体外内皮细胞迁移试验中效果相似，但IFN-α1在器官型脑片培养物中显示出最有效的抗血管生成作用。在体内，将这种基因修饰的胶质母细胞瘤细胞脑内植入后，磁共振成像和死后组织学显示，IFN-α1导致肿瘤体积显著减小。这种抗肿瘤作用的机制很可能是由细胞因子的主要抗血管生成作用引起的，因为IFN-α1的表达导致血管密度明显降低，同时肿瘤实体中出现广泛坏死。脑内植入表达IFN的9L细胞的大鼠中位生存时间增加了两倍，当这些细胞仅占移植肿瘤细胞的1%时，中位生存时间仍显著延长。当50%的移植细胞被表达IFN的骨髓基质细胞取代时，也观察到了类似的效果。这些数据表明，使用细胞载体局部递送IFN-α1是抑制肿瘤诱导血管生成的有效工具。
