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A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice |
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| Authors: | Yung-Yi Chen Nicola J. Brown Rita Jones Claire E. Lewis Ahmed H. Mujamammi Munitta Muthana Michael P. Seed Michael D. Barker |
| Affiliation: | 1. Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK 4. School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK 3. William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry, Queen Mary College University of London, London, EC1M 6BQ, UK 2. Department of Infection and Immunity, Medical School, University of Sheffield, Sheffield, S10 2RX, UK 5. Medicines Research Group, Health, Sport and Bioscience, University of East London, London, E15 4LZ, UK |
| Abstract: | The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist—an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo. |
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