Vascular endothelial growth factor-induced tumor angiogenesis and tumorigenicity in relation to metastasis in a HT1080 human fibrosarcoma cell model.
Although vascular endothelial growth factor (VEGF) is well known to be a potent mitogen for vascular endothelial cells, the role of VEGF in a developmental process of tumor angiogenesis and metastatic potential remains poorly understood. The present study was designed to investigate VEGF-induced vascular formation from a spatiotemporal viewpoint and to analyze VEGF-enhanced metastatic potential using stable clones of HT1080 human fibrosarcoma cells transfected with VEGF cDNA (S) or with vector alone (V). Microangiography revealed massive angiogenesis in the S cell-derived tumors and demonstrated that the angiogenesis occurred not in the tumor itself, but rather around the S cell tumor early after inoculation into the thigh muscles of mice. Thereafter, the angiogenesis extended in and around the tumor. The tumorigenicity of the S cells was higher than the V cells in the subcutaneous (s.c.) space, intraperitoneal space, liver and spleen. However, neither S cells nor V cells metastasized to the liver after an intrasplenic injection. Few apoptotic cells were detected in the S cell tumor, but many apoptotic cells were scattered in the V cell tumor. Our results indicate that VEGF facilitates tumorigenicity in various organs, possibly due to inducing angiogenesis in and around the tumor and preventing tumor cells from undergoing apoptosis, and suggest that VEGF may augment metastatic potential, by accelerating proliferative activity after reaching the target organ. Furthermore, VEGF-induced angiogenesis occurred preferentially around the tumor at an early period of tumor development, followed by neovascularization into the tumor.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan. akr@kuhp.kyoto-u.ac.jp
A
A
Mori
S
S
Arii
M
M
Furutani
K
K
Hanaki
Y
Y
Takeda
T
T
Moriga
Y
Y
Kondo
M J
MJ
Gorrin Rivas
M
M
Imamura
D000818:Animals; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005354:Fibrosarcoma / Q000098:blood supply* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000473:pathology*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013160:Splenic Neoplasms / Q000473:pathology / Q000556:secondary; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors