The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
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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“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]
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“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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Cites
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Self-citationTumor angiogenesis: therapeutic implications
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Self-citationAbnormal blood vessel development and lethality in embryos lacking a single VEGF allele
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Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review)
Naser, R., Fakhoury, I., El‑Fouani, A., Abi‑Habib, R., & El‑Sibai, M. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5471 · Cited by 61
Inhibition of c-Met Reduces Lymphatic Metastasis in RIP-Tag2 Transgenic Mice
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Comparison of gene expression and DNA copy number changes in a murine model of lung cancer
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Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice
Kang, L., Mayes, W. H., James, F. D., Bracy, D. P., & Wasserman, D. H. (2014) · Diabetologia · doi:10.1007/s00125-013-3128-1 · Cited by 48
“The mechanism by which MMP9 stimulates angiogenesis has been suggested to be via the stimulation of production and secretion of VEGF [30, 31].”
Michael, I. P., Saghafinia, S., Tichet, M., Zangger, N., Marinoni, I., Perren, A., & Hanahan, D. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.04.015 · Cited by 42
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“MMP9 has complex effects on the tumor vasculature and can, for example, both promote the formation of tumor vessels and decrease vascular leakiness depending on tumor model and tumor stage ([20]; [25,28,38]).”
BackgroundMethodInfluentialDifferentiation States of Phenotypic Transition of Melanoma Cells Are Revealed by 3D Cell Cultures
Fontana, F., Sommariva, M., Anselmi, M., Bianchi, F., Limonta, P., & Gagliano, N. (2024) · Cells · doi:10.3390/cells13020181 · Cited by 11
“Interestingly, MMP-9 could exert proangiogenic activity by favoring the release of matrix-sequestered angiogenic factors in the early stages of tumor development [82].”
BackgroundCurrent Status of Research on Losartan in Tumour Therapy
Wang, H., Yuan, S., & Wang, H. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70985 · Cited by 11
“Tumour endothelial cell-derived MMP9 further contributes to neo-vascularisation and metastasis by mobilising VEGF from ECM stores [78].”
Metadata
- 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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