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

Cancer Sci. 2007 Apr;98(4):541-8. doi: 10.1111/j.1349-7006.2007.00432.x. Epub 2007 Mar 14.


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.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Disease Progression
  • Female
  • Fibroblast Growth Factor 2 / pharmacology*
  • Glucocorticoids / pharmacology
  • Lymphatic Metastasis
  • Melanoma, Experimental / blood supply*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neovascularization, Pathologic*
  • Skin Neoplasms / blood supply*
  • Stromal Cells / drug effects
  • Vascular Endothelial Growth Factor A / immunology
  • Vascular Endothelial Growth Factor A / pharmacology


  • Antibodies
  • Glucocorticoids
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factor 2