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.

Human tissue inhibitor of mctalloproteinascs-I (TIMP-I), but not TlMP-2, has potent growth-promoting activity for a wide range of human and bovine cells, TLMP-1 seems to be a new cell-growth factor in serum and to stimulate the cells indcpendcntly of its inhibilory activity.Tissue inhibitor of mctalloprotcinasc (TIMP-1 and TIMP-2

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Mammalian cell-surface peptidases participate in the postsecretory processing and metabolism of neuropeptides and peptide hormones. Neutral endopeptidase-24.11 (NEP) is the prototype of a family of zinc metallopeptidases that also includes the endothelin-converting enzymes (ECE) and which are structurally related to the bacterial enzymes thermolysin and lactococcal endopeptidase. Two other mammalian gene products exhibit strong homology with NEP: the erythrocyte cell-surface antigen, KELL; and the putative product of the PEX gene, which has been associated with X-linked hypophosphatemic rickets. No enzymic activity has yet been attributed to KELL and PEX proteins, and they remain peptidases in search of a substrate. A wide range of biologically active peptide substrates has been described for NEP, of which the enkephalins and the atrial natriuretic peptide family have assumed greatest significance. Endothelin-converting enzyme catalyses the final step in the biosynthesis of the vasoconstrictor peptide, endothelin (ET). Like NEP, it is a type II integral membrane protein, but is expressed predominantly in endothelial cells. Isoforms of ECE (ECE-1alpha, ECE-1beta, and ECE-2) exist that differ in a number of characteristics. In particular, ECE-1, through the paracrine effects of ET-1, may contribute to the proliferation of smooth muscle after angioplasty and to the development of human atherosclerosis. Inhibitors of ECE and NEP may have important therapeutic applications in cardiovascular and renal medicine.

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