Angiogenesis inhibitors overcome tumor induced endothelial cell anergy

Int J Cancer. 1999 Jan 18;80(2):315-9. doi: 10.1002/(sici)1097-0215(19990118)80:2<315::aid-ijc23>;2-l.


We report here that tumor angiogenesis-mediated endothelial cell (EC) anergy can be overcome by inhibitors of angiogenesis. We found previously that tumor growth, known to be dependent on angiogenesis, results in down-regulation of endothelial adhesion molecules and tumor EC anergy to inflammatory signals. We hypothesized that counteracting angiogenesis induces re-expression of adhesion molecules and normalizes responses to inflammatory cytokines. Here, we present data to show that the angiogenesis inhibitor platelet factor-4 (PF4) is able to prevent basic fibroblast growth factor (bFGF)-induced down-regulation of intercellular adhesion molecule-1 (ICAM-1). Furthermore, PF4 restores ICAM-1 expression following bFGF-induced down-regulation of ICAM-1. This PF4 effect occurs at the protein level and the RNA level and it has functional impact on leukocyte adhesion. In addition, PF4 overcomes the tumor-induced EC anergy to inflammatory signals such as tumor necrosis factor alpha (TNF alpha). Our findings may be the basis of new cancer therapies by combining anti-angiogenic therapy and immunotherapy to decrease blood vessel formation and to increase the effectiveness of inflammatory reactions against tumors.

MeSH terms

  • Animals
  • Cattle
  • Cell Adhesion
  • Clonal Anergy
  • Down-Regulation
  • Endothelium, Vascular / drug effects*
  • Fibroblast Growth Factor 2 / antagonists & inhibitors
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leukocytes / cytology
  • Neovascularization, Pathologic / drug therapy*
  • Platelet Factor 4 / pharmacology*


  • Fibroblast Growth Factor 2
  • Intercellular Adhesion Molecule-1
  • Platelet Factor 4