Vascular endothelial growth factor vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma
Vascular endothelial growth factor vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma
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DOI：
10.1073/pnas.94.3.979
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发表时间：
1997-02-04
影响因子：
11.1
通讯作者：
Gill, PS
中科院分区：
文献类型：
--
作者：
Masood, R;Cai, J;Gill, PS
卡波西肉瘤 (KS) 是与 HIV-1 感染相关的最常见肿瘤，近 30% 的病例会发生这种肿瘤，该肿瘤的主要特征是异常血管化以及内皮细胞和梭形（肿瘤）细胞的增殖。 KS衍生的梭形细胞在裸鼠皮下接种时会诱导血管损伤并表现出血管通透性增强。这一发现表明血管生成和毛细血管通透性在 KS 的发生和进展中发挥着核心作用。在这项研究中，我们发现 AIDS-KS 细胞系比人脐静脉内皮细胞或人主动脉平滑肌细胞表达更高水平的血管内皮生长因子/血管通透性因子 (VEGF/VGF)。 AIDS-KS细胞和原发肿瘤组织也表达高水平的VEGF受体Flt-1和KDR，而同一患者的正常皮肤没有表现出任何表达。我们进一步证明VEGF反义寡核苷酸AS-1和AS-3特异性阻断VEGF mRNA和蛋白的产生，并以剂量依赖性方式抑制KS细胞生长。此外，VEGF反义寡核苷酸特异性抑制裸鼠中KS细胞的生长。这些结果表明VEGF是AIDS-KS细胞的自分泌生长因子。据我们所知，这是第一份表明 VEGF 在人类肿瘤中充当生长刺激剂的报告，因此 VEGF 或其同源受体的抑制剂可能成为治疗干预的候选药物。
Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases, The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression, We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor, Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.