Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor
Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor
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DOI：
10.1073/pnas.93.16.8502
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发表时间：
1996-08-06
影响因子：
11.1
通讯作者：
Cavenee, WK
中科院分区：
文献类型：
--
作者：
Cheng, SY;Huang, HJS;Cavenee, WK
从宿主的正常微血管发展新的毛细血管网络似乎是实体瘤生长所必需的。肿瘤细胞通过产生血管生成的抑制剂和正效应物来影响这一过程。在后者中，血管内皮生长因子（VEGF）被认为是主要的积极生理效应。在这里，我们直接在脑肿瘤，多形性胶质母细胞瘤，一种高度血管化的人类癌症中测试了这个假设。我们将一种反义VEGF表达构建体引入胶质母细胞瘤细胞，发现(i) VEGF mRNA和蛋白水平显著降低，（ii）修饰后的细胞不能分泌足够的因子来吸引原代人微血管内皮细胞，（iii）修饰后的细胞不能在免疫缺陷动物中维持肿瘤生长。（iv）体内血管形成密度降低，与VEGF分泌减少和肿瘤形成直接相关。此外，恢复了VEGF分泌能力的逆转细胞恢复了这些致瘤特性。这些结果表明VEGF在胶质母细胞瘤中起主要的血管生成作用。
The development of new capillary networks from the normal microvasculature of the host appears to be required for growth of solid tumors. Tumor cells influence this process by producing both inhibitors and positive effectors of angiogenesis. Among the latter, the vascular endothelial growth factor (VEGF) has assumed prime candidacy as a major positive physiological effector. Here, we have directly tested this hypothesis in the brain tumor, glioblastoma multiforme, one of the most highly vascularized human cancers. We introduced an antisense VEGF expression construct into glioblastoma cells and found that (i) VEGF mRNA and protein levels were markedly reduced, (ii) the modified cells did not secrete sufficient factors so as to be chemoattractive for primary human microvascular endothelial cells, (iii) the modified cells were not able to sustain tumor growth in immunodeficient animals, and (iv) the density of in vivo blood vessel formation was reduced in direct relation to the reduction of VEGF secretion and tumor formation. Moreover, revertant cells that recovered the ability to secrete VEGF regained each of these tumorigenic properties. These results suggest that VEGF plays a major angiogenic role in glioblastoma.