Yoshiji Hitoshi, Kuriyama Shigeki, Yoshii Junichi, Ikenaka Yasuhide, Noguchi Ryuichi, Hicklin Daniel J, Huber James, Nakatani Toshiya, Tsujinoue Hirohisa, Yanase Koji, Imazu Hiroo, Fukui Hiroshi
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara Nara, Japan.
Hepatology. 2002 Apr;35(4):834-42. doi: 10.1053/jhep.2002.32541.
The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are potent and representative factors involved in tumor development. It has been reported that bFGF and VEGF showed a synergistic effect in both in vitro and in vivo angiogenesis. However, the interaction of these factors on tumor development and angiogenesis, including hepatocellular carcinoma (HCC), has not yet been elucidated. In this study, we examined the combined effect of bFGF and VEGF overexpression by means of a combination of a retroviral tetracycline (tet)-regulated (Retro-Tet) gene expression system, which can manipulate the gene expression in vivo by providing tet in the drinking water, and a conventional plasmid gene expression system. In an allograft study, bFGF and VEGF overexpression synergistically increased tumor growth and angiogenesis in the murine HCC cells. This synergistic effect also was found in established tumors. VEGF messenger RNA (mRNA) expression in the tumor was increased 3.1-fold by bFGF-overexpression, and the bFGF-induced tumor development was significantly attenuated by treatment with KDR/Flk-1 neutralizing monoclonal antibody. In conclusion, these results suggest that bFGF synergistically augments VEGF-mediated HCC development and angiogenesis at least partly by induction of VEGF through KDR/Flk-1.
任何实体瘤的生长都依赖于血管生成。在已知的血管生成因子中，碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）是参与肿瘤发展的强效且具有代表性的因子。据报道，bFGF和VEGF在体外和体内血管生成中均显示出协同作用。然而，这些因子在包括肝细胞癌（HCC）在内的肿瘤发展和血管生成中的相互作用尚未阐明。在本研究中，我们通过逆转录病毒四环素（tet）调控（Retro-Tet）基因表达系统（该系统可通过在饮用水中提供tet来在体内操纵基因表达）与传统质粒基因表达系统相结合的方法，研究了bFGF和VEGF过表达的联合效应。在一项同种异体移植研究中，bFGF和VEGF过表达协同增加了小鼠肝癌细胞中的肿瘤生长和血管生成。在已形成的肿瘤中也发现了这种协同效应。bFGF过表达使肿瘤中VEGF信使核糖核酸（mRNA）表达增加了3.1倍，并且用KDR/Flk-1中和单克隆抗体治疗可显著减弱bFGF诱导的肿瘤发展。总之，这些结果表明，bFGF至少部分地通过KDR/Flk-1诱导VEGF，协同增强VEGF介导的肝癌发展和血管生成。
