Matrix metalloproteinase-9 Triggers the Angiogenic Switch During Carcinogenesis

Nat Cell Biol. 2000 Oct;2(10):737-44. doi: 10.1038/35036374.

Abstract

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetamides / pharmacology
  • Animals
  • Cell Transformation, Neoplastic*
  • Endothelial Growth Factors / isolation & purification
  • Genes, Switch
  • Islets of Langerhans / pathology*
  • Lymphokines / isolation & purification
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic*
  • Pancreatic Neoplasms / blood supply*
  • Receptor Protein-Tyrosine Kinases / isolation & purification
  • Receptors, Growth Factor / isolation & purification
  • Receptors, Vascular Endothelial Growth Factor
  • Signal Transduction
  • Tissue Distribution
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Acetamides
  • Endothelial Growth Factors
  • Lymphokines
  • R 94138
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Matrix Metalloproteinase 9