Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.
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.
Bergers
G
G
Department of Biochemistry and Biophysics, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.
Brekken
R
R
McMahon
G
G
Vu
T H
TH
Itoh
T
T
Tamaki
K
K
Tanzawa
K
K
Thorpe
P
P
Itohara
S
S
Werb
Z
Z
Hanahan
D
D
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000302:isolation & purification; D005812:Genes, Switch; D007515:Islets of Langerhans / Q000473:pathology*; D008222:Lymphokines / Q000302:isolation & purification; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply*; D020794:Receptor Protein-Tyrosine Kinases / Q000302:isolation & purification; D017978:Receptors, Growth Factor / Q000302:isolation & purification; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000081:Acetamides; D016228:Endothelial Growth Factors; D008222:Lymphokines; C117981:R 94138; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D020780:Matrix Metalloproteinase 9