Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal
Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal
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DOI：
10.1073/pnas.94.16.8761
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发表时间：
1997-08-05
影响因子：
11.1
通讯作者：
Keshet, E
中科院分区：
文献类型：
--
作者：
Benjamin, LE;Keshet, E
我们最近已经表明，VEGF在发育性新血管形成期间作为新形成血管的存活因子起作用，但不是维持成熟血管所必需的。由于扩张的肿瘤含有显著部分的新形成和重塑血管，我们检查了VEGF的突然撤回是否会导致预先形成的肿瘤血管的消退，在异种移植的C6神经胶质瘤细胞中使用四环素调节的VEGF表达系统，我们表明，关闭VEGF的产生导致内皮细胞从预先形成的血管壁脱离，随后通过凋亡导致其死亡，然后血管塌陷导致血管扩张和广泛的肿瘤坏死。这些结果表明，血管存活因子的强制撤回可以应用于已建立的肿瘤中的靶向预形成的肿瘤血管系统。该系统还用于检查由VEGF过表达引起的表型。当转染的VEGF cDNA的表达持续“开启”时，肿瘤变得过度血管化，具有异常大的血管，推测是由于过度融合引起的。肿瘤的坏死程度明显较低，表明这些肿瘤的坏死是血管生成不足的结果。
We have recently shown that VEGF functions as a survival factor for newly formed vessels during developmental neovascularization, but is not required for maintenance of mature vessels, Reasoning that expanding tumors contain a significant fraction of newly formed and remodeling vessels, we examined whether abrupt withdrawal of VEGF will result in regression of preformed tumor vessels, Using a tetracycline-regulated VEGF expression system in xenografted C6 glioma cells, we showed that shutting off VEGF production leads to detachment of endothelial cells from the walls of preformed vessels and their subsequent death by apoptosis, Vascular collapse then leads to hemorrhages and extensive tumor necrosis. These results suggest that enforced withdrawal of vascular survival factors can be applied to target preformed, tumor vasculature in established tumors, The system was also used to examine phenotypes resulting from over-expression of VEGF. When expression of the transfected VEGF cDNA was continuously ''on,'' tumors became hyper-vascularized with abnormally large vessels, presumably arising from excessive fusions. Tumors were significantly less necrotic, suggesting that necrosis in these tumors is the result of insufficient angiogenesis.