Cited by 2,797Angiogenesis and VEGF in CancerProtease and Inhibitor MechanismsTGF-β signaling in diseases

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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

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Bergers, Gabriele, Brekken, Rolf, McMahon, Gerald, Vu, Thiennu H., Itoh, Takeshi, Tamaki, Kazuhiko, Tanzawa, Kazuhiko, Thorpe, Philip, Itohara, Shigeyoshi, Werb, Zena, Hanahan, Douglas·2000·Nature Cell Biology

DOI 10.1038/35036374PMC PMC2852586

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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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BackgroundInfluential
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Authors: Bergers, G., Brekken, R., McMahon, G., Vu, T. H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., & Hanahan, D.
Affiliations: University of California, San Francisco (US)
Hope Heart Institute (US)
Kyoto University (JP)
Harold C. Simmons Comprehensive Cancer Center (US)
RIKEN Center for Brain Science (JP)
Corresponding author: Hanahan, Douglas
ORCID: Bergers, Gabriele
Brekken, Rolf
Itohara, Shigeyoshi
Werb, Zena
Hanahan, Douglas
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2000-09-20
Volume: 2
Issue: 10
Pages: 737-744
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/35036374
PMC: PMC2852586
OpenAlex: W1574172480
Cited by: 2,797
References: 45
Citations by year: 2026: 37 · 2025: 55 · 2024: 76 · 2023: 74 · 2022: 96 · 2021: 90 · 2020: 92 · 2019: 88 · 2018: 82 · 2017: 107 · 2016: 110 · 2015: 98 · 2014: 133 · 2013: 140 · 2012: 137
FWCI: 36.56
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P01CA072006, R01CA057621)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: MMP-9, angiogenic switch, vascular endothelial growth factor, VEGF signaling, MMP-2, urokinase, tumor angiogenesis, tumor growth, matrix metalloproteinase inhibitors, SU5416, transgenic mice
MeSH terms: Acetamides, Animals, Cell Transformation, Neoplastic, Genes, Switch, Islets of Langerhans, Lymphokines, Mice, Transgenic, Neovascularization, Pathologic, Pancreatic Neoplasms, Tissue Distribution, Signal Transduction, Endothelial Growth Factors, Receptors, Growth Factor, Matrix Metalloproteinase 9, Receptor Protein-Tyrosine Kinases, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice

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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

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