title: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bergers
authors.forename: R
authors.initials: R
authors.lastname: Brekken
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.forename: T H
authors.initials: TH
authors.lastname: Vu
authors.forename: T
authors.initials: T
authors.lastname: Itoh
authors.forename: K
authors.initials: K
authors.lastname: Tamaki
authors.forename: K
authors.initials: K
authors.lastname: Tanzawa
authors.forename: P
authors.initials: P
authors.lastname: Thorpe
authors.forename: S
authors.initials: S
authors.lastname: Itohara
authors.forename: Z
authors.initials: Z
authors.lastname: Werb
authors.forename: D
authors.initials: D
authors.lastname: Hanahan
mesh_terms: 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
chemical_list: 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