Joint Study on Angiogenesis and Growth Factor Responses

M.Kuwano，M.Ono，Y.Sato和K.Kohno与K.Miyazono，D.Rifkin和H-f.Kung合作进行了关于血管生成和生长因子反应的联合研究，我们获得了以下结果。我们最近建立了一种体外血管生成模型，其中血管内皮细胞在I型胶原凝胶上的内室与其他类型的细胞在外室共培养。体外培养的人软骨细胞可抑制EGF/TGF α依赖的血管内皮细胞小管形成。这种软骨细胞诱导的小管形成的抑制被抗TGF β抗体部分消除，提示TGF β部分参与了人软骨细胞依赖的无血管化. H-ras癌基因的导入降低了小鼠Balb/3 T3细胞表面EGF受体的结合活性。EGF受体基因表达在H-ras转染子中被废除，但V-myc的共同引入恢复了EG ...更多信息 引入编码转录失活产物的显性负性c-jun突变体抑制H-ras依赖的AP-1（Jun/Fos）诱导，并恢复H-ras癌基因对EGF结合的下调.氧自由基在包括炎症在内的各种病理条件下被诱导。用过氧化氢（H_2O_2）处理人微血管内皮细胞可诱导肾小管样结构的形成，而联合应用NF κ B的反义序列可抑制H_2O_2依赖的肾小管样结构的形成。氧化刺激后血管内皮细胞的管状形态发生似乎与NF κ B和IL 8.4相关。Irogladine在临床上用作抗gastricer剂，浓度为10 μ M<-6>至10 μ <-4>M时，可特异性抑制血管内皮细胞的细胞增殖和管形成。当人肿瘤细胞移植到小鼠体内时，口服30 - 120 mg/kg/天的伊索拉定可抑制肿瘤生长和肿瘤血管生成。少

M.Kuwano, M.Ono, Y.Sato and K.Kohno have done the joint study on angiogenesis and growth factor responses in collaboration with K.Miyazono, D.Rifkin and H-f.Kung, and we obtained results as described below.1. We have recently established angiogenesis model in vitro in wihch vascular endothelial cells on type I collagen gel in an inner chamber are co-cultured with other types of cells in an outer chamber. EGF/TGFalpha dependent tube formation of vascular endothelial cells was inhibited when human chondrocytes were co-cultured in the outer chamger. This chondrocype-induced inhibition of tube fomation was partly abrogated by administraion of anti-TGF beta antibody, suggesting that TGF beta is partly involved in the human chondrocyte-dependent avascularily.2. Introduction of H-ras oncogene decreased the EGF binding activity to all surface EGF receptor in mouse Balb/3T3 cells. EGF receptor gene expression was abrogated in the H-ras transfectants, but co-introduction of V-myc restored the EG … More F receptor to normal levels.Introduction of dominant-negative c-jun mutant encoding a transcriptionally inactive product inhibited the H-ras dependent AP-1 (Jun/Fos) induction, and also restored down-regulation of EGF binding by H-ras oncogene.3. Oxygen radicals are induced under various pathological conditions including inflamation. Treatment with hydrogen peroxide (H_2O_2) of human microvascular endothelial cells induced development of tube-like structres, and co-administration of antisense sequence of NFkB inhibited the H_2O_2 dependent tubular morphogenesis was almost completely abrogated when anti-IL8 antibody was present. Tubular morphogenesis of vascular endothelial cells after the oxidative stimuli appeared to be associated with NFkB and IL8.4. Irogladine used clinically as an anti-gasTriculcer agent at 10 ^<-6> to 10^<-4>M inhibited specifically cell proliferation and tube formation of vascular endothelial cells. Oral administration of irsogladine at 30 to 120 mg/kg/day inhibited both tumor growth and tumor angiogenesis when human tumor cells were transplanted in mice. Less