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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Nature Cell Biology volume 2, pages 737–744 (2000)Cite this article

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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Figure 1: Inhibition of VEGF activity during carcinogenesis in islet cells.
Figure 2: Changes in VEGF localization and its involvement in angiogenesis.
Figure 3: Zymography profiles of extracellular proteinase activity during tumorigenesis.
Figure 4: MMP-9 can activate angiogenesis and release VEGF from normal islets.
Figure 5: Localization of MMP-9 in angiogenic stages.
Figure 6: Comparative genetic and pharmacogenetic analyses of the angiogenic switch and tumour growth.
Figure 7: Characterization of protease-deficient angiogenic islets and tumours.

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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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Author notes

  1. Takeshi Itoh

    Present address: Shionogi Institute for Medical Science, Shionogi & Co. Ltd, 12–4 Sagisu 5-Chome, Fukushima-ku, Osaka, 553-0002, Japan

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Gabriele Bergers & Douglas Hanahan

  2. Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Thiennu H. Vu

  3. Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Zena Werb

  4. Hormone Research Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Gabriele Bergers & Douglas Hanahan

  5. UCSF Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, California, USA

    Zena Werb & Douglas Hanahan

  6. Department of Vascular Biology, The Hope Heart Institute, 1124 Columbia Street, Seattle, 98104, Washington, USA

    Rolf Brekken

  7. SUGEN Inc., 230 East Grand Avenue, South San Francisco, 94080-4811, California, USA

    Gerald McMahon

  8. Institute for Virus Research, Kyoto University, 53 Kawahara, Syogo-in, Sakyo-ku, 606-8397, Kyoto, Japan

    Takeshi Itoh

  9. Sankyo Co. Ltd, 2-58 Hiromachi 1-Chome, Shinagawa-Ku, 140-8710, Tokyo, Japan

    Kazuhiko Tamaki & Kazuhiko Tanzawa

  10. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, 75235-9111, Texas, USA

    Philip Thorpe

  11. Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, 351-0198, Japan

    Shigeyoshi Itohara

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Correspondence to Douglas Hanahan.

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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, 737–744 (2000). https://doi.org/10.1038/35036374

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