Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis

J Clin Invest. 2007 Oct;117(10):2766-77. doi: 10.1172/JCI32479.


Tumors produce multiple growth factors, but little is known about the interplay between various angiogenic factors in promoting tumor angiogenesis, growth, and metastasis. Here we show that 2 angiogenic factors frequently upregulated in tumors, PDGF-BB and FGF2, synergistically promote tumor angiogenesis and pulmonary metastasis. Simultaneous overexpression of PDGF-BB and FGF2 in murine fibrosarcomas led to the formation of high-density primitive vascular plexuses, which were poorly coated with pericytes and VSMCs. Surprisingly, overexpression of PDGF-BB alone in tumor cells resulted in dissociation of VSMCs from tumor vessels and decreased recruitment of pericytes. In the absence of FGF2, capillary ECs lacked response to PDGF-BB. However, FGF2 triggers PDGFR-alpha and -beta expression at the transcriptional level in ECs, which acquire hyperresponsiveness to PDGF-BB. Similarly, PDGF-BB-treated VSMCs become responsive to FGF2 stimulation via upregulation of FGF receptor 1 (FGFR1) promoter activity. These findings demonstrate that PDGF-BB and FGF2 reciprocally increase their EC and mural cell responses, leading to disorganized neovascularization and metastasis. Our data suggest that intervention of this non-VEGF reciprocal interaction loop for the tumor vasculature could be an important therapeutic target for the treatment of cancer and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Capillaries
  • Cell Movement
  • Cell Proliferation
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology
  • Fibrosarcoma / blood*
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology*
  • Humans
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, SCID
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Pericytes / metabolism
  • Pericytes / pathology
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • Platelet-Derived Growth Factor / pharmacology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-sis
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Signal Transduction


  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Fibroblast Growth Factor 2
  • Becaplermin
  • Receptor, Fibroblast Growth Factor, Type 1