Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
Open accessAbstract
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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Neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines.
“Genetic and functional experiments indicate that neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines11,23–26.”
From Inflammation and cancer (2002) · cites this paper as [26]
MMP-9 breaks down fibrous collagen matrix to make space for new blood vessels and releases matrix-bound VEGF.
“Furthermore, the actions of MMP-9 both break down the fibrous collagen matrix to make space for new blood vessels and release matrix-bound VEGF (53).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [53]
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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
- Venue
- Nature Cell Biology
- Published
- 2000-09-20
- Volume
- 2
- Issue
- 10
- Pages
- 737-744
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- 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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