Blockage of VEGF-induced angiogenesis by preventing VEGF secretion
Blockage of VEGF-induced angiogenesis by preventing VEGF secretion
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DOI：
10.1161/01.res.0000129194.61747.bf
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发表时间：
2004-06-11
影响因子：
20.1
通讯作者：
Cao, YH
中科院分区：
文献类型：
--
作者：
Björndahl, M;Cao, RH;Cao, YH
血管内皮生长因子（VEGF）/血管通透性因子是多种病理组织中最常表达的血管生成因子之一。开发VEGF拮抗剂已成为治疗血管生成依赖性疾病的重要途径。在这里，我们描述了一种新的抗VEGF策略，通过阻止VEGF的分泌。我们利用胎盘生长因子（PlGF）-1，缺乏可检测的血管生成活性的VEGF家族的成员，在共表达两种因子的细胞中优先与VEGF形成细胞内异二聚体的事实。我们构建了一个逆转录病毒载体，含有人PlGF-1或VEGF的C-末端KDEL序列，这是一个哺乳动物的内质网滞留信号。用逆转录-hPlGF-1-KDEL构建体转导鼠刘易斯肺癌细胞几乎完全消除了肿瘤生长。与显著的抗肿瘤作用一致，大多数小鼠VEGF分子保持为细胞内mVEGF/hPlGF-1异二聚体，并且仅分泌可忽略量的mVEGF同二聚体。结果，在表达hPlGF-1-KDEL的肿瘤中，血管保持在非常低的数量并且缺乏分支和毛细血管网络。将hVEGF-KDEL构建体基因转移到肿瘤细胞中同样产生显著的抗肿瘤作用。因此，我们的研究提供了一种新的抗血管生成的方法，通过阻止VEGF的分泌。
Vascular endothelial growth factor (VEGF)/vascular permeability factor is one of the most frequently expressed angiogenic factors in several pathological tissues. Development of VEGF antagonists has become an important approach in the treatment of angiogenesis-dependent diseases. Here we describe a novel anti-VEGF strategy by preventing the secretion of VEGF. We utilize the fact that placenta growth factor (PlGF)-1, a member of the VEGF family lacking detectable angiogenic activity, preferentially forms intracellular heterodimers with VEGF in cells coexpressing both factors. We constructed a retroviral vector containing human PlGF-1 or VEGF with a C-terminal KDEL sequence, which is a mammalian retention signal for the endoplasmic reticulum. Transduction of murine Lewis lung carcinoma cells with the retro-hPlGF-1-KDEL construct almost completely abrogated tumor growth. Consistent with the dramatic antitumor effect, most mouse VEGF molecules remained as intracellular mVEGF/hPlGF-1 heterodimers, and only a negligible amount of mVEGF homodimers were secreted. As a result, in hPlGF-1-KDEL-expressing tumors, blood vessels remained at very low numbers and lacked branching and capillary networks. Gene transfer of a hVEGF-KDEL construct into tumor cells likewise produced a dramatic antitumor effect. Thus, our study provides a novel antiangiogenic approach by preventing the secretion of VEGF.