Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

During carcinogenesis of pancreatic islets in transgenic mice, an angiogeni c switch activates the quiescent vasculature. Paradoxically, vascular endot helial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs an giogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatin ase-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 ablatio n 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 result s show that MMP-9 is a component of the angiogenic switch.