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.
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Acknowledgements
We thank British Biotech Pharmaceuticals, Oxford, UK, for BB-94. We also thank E. Soliven, C. Skinner and O. Behrendtsen for excellent technical assistance, A. McMillan for help with statistical analysis, W. Ruth and T. Schoop of Biomed Arts for help with figures, D. Daniel and L. Coussens for valuable discussions, and B. Bowes and J. Folkman for support and encouragement. This work was funded by grants from the National Cancer Institute.
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Bergers, G., Brekken, R., McMahon, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2, 737â744 (2000). https://doi.org/10.1038/35036374
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DOI: https://doi.org/10.1038/35036374
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