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
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetamides / pharmacology
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Animals
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Cell Transformation, Neoplastic*
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Endothelial Growth Factors / isolation & purification
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Genes, Switch
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Islets of Langerhans / pathology*
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Lymphokines / isolation & purification
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Transgenic
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Neovascularization, Pathologic*
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Pancreatic Neoplasms / blood supply*
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Receptor Protein-Tyrosine Kinases / isolation & purification
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Receptors, Growth Factor / isolation & purification
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Receptors, Vascular Endothelial Growth Factor
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Signal Transduction
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Tissue Distribution
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Acetamides
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Endothelial Growth Factors
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Lymphokines
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R 94138
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Matrix Metalloproteinase 9