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TIMP-2 mediates cell surface binding of MMP-2
M L Corcoran1, M R Emmert-Buck, J L McClanahan
1Extracellular Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Advances in Experimental Medicine and Biology
|January 1, 1996
Summary
Tissue inhibitor of metalloproteinase-2 (TIMP-2) facilitates neoplastic cell invasion by binding gelatinase A to the cell surface. This interaction promotes cancer cell invasion, which can be suppressed by adding more TIMP-2.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Neoplastic cell invasion is a critical process in cancer metastasis.
- Matrix metalloproteinases (MMPs), like gelatinase A, play a role in extracellular matrix degradation.
- Tissue inhibitor of metalloproteinases-2 (TIMP-2) is a known inhibitor of gelatinase A.
Purpose of the Study:
- To elucidate the mechanism of neoplastic cell invasion.
- To investigate the binding of TIMP-2, gelatinase A, and their complex to cancer cells.
- To correlate binding characteristics with the invasive capacity of neoplastic cells.
Main Methods:
- Binding studies using recombinant TIMP-2 (rTIMP-2), recombinant gelatinase A (rGelatinase A), and the TIMP-2/gelatinase A complex.
- Experiments conducted on malignant human breast cancer cells (MDA-MB-435) and fibrosarcoma cells.
- Modified Boyden chamber assay to assess matrix invasion.
- Competition studies to determine binding characteristics.
Main Results:
- Gelatinase A and the TIMP-2/gelatinase A complex bind to the cell surface via TIMP-2.
- Localization of gelatinase A (latent or active) on MDA-MB-435 cells facilitated invasion through a matrigel barrier.
- Exogenous addition of rTIMP-2 suppressed the enhanced invasion of these cancer cells.
- Cancer cells appear to activate the pro-enzyme-inhibitor complex on their surface for invasion.
Conclusions:
- TIMP-2 binding to gelatinase A on the neoplastic cell surface is crucial for facilitating invasion.
- The TIMP-2/gelatinase A complex, when localized to the cell surface, contributes to cancer cell invasion.
- TIMP-2 can act as a suppressor of cancer cell invasion by inhibiting this mechanism.