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

doi:10.1038/35036374

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 journal › Article › peer-review

2343 Scopus citations

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.

Original language	English (US)
Pages (from-to)	737-744
Number of pages	8
Journal	Nature cell biology
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/35036374
State	Published - Oct 2000

ASJC Scopus subject areas

Cell Biology

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title = "Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis",

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.",

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

note = "Funding Information: 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. Correspondence and requests for materials should be addressed to D.H.",

year = "2000",

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doi = "10.1038/35036374",

language = "English (US)",

volume = "2",

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AU - Bergers, Gabriele

AU - Brekken, Rolf

AU - McMahon, Gerald

AU - Vu, Thiennu H.

AU - Itoh, Takeshi

AU - Tamaki, Kazuhiko

AU - Tanzawa, Kazuhiko

AU - Thorpe, Philip

AU - Itohara, Shigeyoshi

AU - Werb, Zena

AU - Hanahan, Douglas

N1 - Funding Information: 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. Correspondence and requests for materials should be addressed to D.H.

PY - 2000/10

Y1 - 2000/10

N2 - 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.

AB - 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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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

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