Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Gabriele Bergers, Rolf Brekken, Gerald McMahon, Thiennu H. Vu, Takeshi Itoh, Kazuhiko Tamaki, Kazuhiko Tanzawa, Philip Thorpe, Shigeyoshi Itohara, Zena Werb, Douglas Hanahan

Research output: Contribution to journalArticlepeer-review

2288 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)737-744
Number of pages8
JournalNature cell biology
Issue number10
StatePublished - Oct 2000

ASJC Scopus subject areas

  • Cell Biology


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