Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma.
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara Nara, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Hicklin
Daniel J
DJ
Huber
James
J
Nakatani
Toshiya
T
Tsujinoue
Hirohisa
H
Yanase
Koji
K
Imazu
Hiroo
H
Fukui
Hiroshi
H
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology*; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007279:Injections, Subcutaneous; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology*; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000379:methods; D009389:Neovascularization, Pathologic / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D012190:Retroviridae / Q000235:genetics; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011500:Protein Synthesis Inhibitors; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D013752:Tetracycline