ANTISENSE OLIGONUCLEOTIDES AS INHIBITORS OF TUMOR-INDUCED ANGIOGENESIS

我们已经调查了ETS家族成员ETS1在 血管生成。血管内皮细胞生长因子(VEGF)增加 人脐静脉中ETS1mRNA和蛋白水平的研究 内皮细胞(HUVEC)。研究还发现，血管内皮细胞生长因子也能刺激 人脐静脉内皮细胞通过基质或明胶涂层的迁移能力 膜。这种血管内皮生长因子诱导的侵袭性被反义寡核苷酸抑制 ETS1寡核苷酸，但不受感官或错配对照。 综上所述，这些观察显示了ETS1的直接作用 血管生成中的基因。 我们通过HPV-16E6-E7基因建立了永生化的人脐静脉内皮细胞 进一步转化了一株永生化但不致瘤的品系(4-5-2G) 通过v-ki-ras基因产生致瘤细胞系。单单E6或E7就可以 不会产生永生的线条，而是延长了细胞的寿命。 4-5-2G呈鹅卵石状，发育成 到达汇合处时为毛细管状结构。它表达了 因子，结合DiI-Ac-低密度脂蛋白，表达整合素亚基 图案与内皮来源一致。这些结果表明 4-5-2G可以作为内皮细胞生物学的模型。

We have investigated the role of one ets family member, ETS1, in the angiogenesis. Vascular endothelial growth factor (VEGF) increases the level of ETS1 mRNA and protein levels in human umbilical vein endothelial cells (HUVEC). VEGF was also found to stimulate the ability of HUVEC to migrate through Matrigel or gelatin coated membranes. This VEGF-induced invasiveness was inhibited by antisense ETS1 oligonucleotides but not by a sense or mismatch controls. Together, these observations demonstrate a direct role for the ETS1 gene in angiogenesis. We have established immortalized HUVEC by the HPV-16 E6-E7 genes and further transformed one immortalized but nontumorigenic line (4-5-2G) by v-Ki-ras to produce tumorigenic cell lines. E6 or E7 alone could not produce immortalized lines but extended the life span of the cells. 4-5-2G had a cobblestone morphology that developed into a capillary-like tube structure upon reaching confluence. It expressed factor VIII, took up DiI-Ac-LDL, and expressed integrin subunits in a pattern consistent with an endothelial origin. These results indicate that 4-5-2G may serve as a model for endothelial cell biology.