Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization.
Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.
Tsunoda
Satoshi
S
Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., 301, Gensuke, Fujieda, Shizuoka, 426-0088, Japan. tsunoda_satoshi@kaken.co.jp
Nakamura
Toshiyuki
T
Sakurai
Hiroaki
H
Saiki
Ikuo
I
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000098:blood supply*; D017154:Stromal Cells / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000494:pharmacology
D000906:Antibodies; D005938:Glucocorticoids; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2