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MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth
N E Sounni1, L Devy, A Hajitou
1Laboratory of Tumor and Development Biology, Laboratory of Connective Tissues Biology, University of Liège, Sart Tilman, B-4000 Liège, Belgium.
Abstract:
Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly by activating pro-MMP2. We investigated the effects of MT1-MMP overexpression on in vitro and in vivo properties of human breast adenocarcinoma MCF7 cells, which do not express MT1-MMP or MMP-2. MT1-MMP and MMP-2 cDNAs were either transfected alone or cotransfected. All clones overexpressing MT1-MMP 1) were able to activate endogenous or exogenous pro-MMP-2, 2) displayed an enhanced in vitro invasiveness through matrigel-coated filters independent of MMP-2 transfection, 3) induced the rapid development of highly vascularized tumors when injected subcutaneously in nude mice, and 4) promoted blood vessels sprouting in the rat aortic ring assay. These effects were observed in all clones overexpressing MT1-MMP regardless of MMP-2 expression levels, suggesting that the production of MMP-2 by tumor cells themselves does not play a critical role in these events. The angiogenic phenotype of MT1-MMP-producing cells was associated with an up-regulation of VEGF expression. These results emphasize the importance of MT1-MMP during tumor angiogenesis and open new opportunities for the development of anti-angiogenic strategies combining inhibitors of MT1-MMP and VEGF antagonists.
Insights
Overexpressing membrane type 1 metalloprotease (MT1-MMP) in breast cancer cells enhances tumor growth and vascularization, independent of MMP-2. This highlights MT1-MMP
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Membrane type 1 metalloprotease (MT1-MMP) is crucial for extracellular matrix remodeling and activates pro-MMP-2.
- MT1-MMP's role in tumor angiogenesis and invasiveness is not fully understood, especially in breast cancer cells lacking endogenous expression.
Purpose of the Study:
- To investigate the impact of MT1-MMP overexpression on the in vitro and in vivo characteristics of human breast adenocarcinoma MCF7 cells.
- To determine the role of MT1-MMP in tumor cell invasiveness, vascularization, and angiogenesis, with or without co-expression of MMP-2.
Main Methods:
- Transfection of MT1-MMP and MMP-2 cDNAs into MCF7 cells.
- Assessment of in vitro invasiveness using matrigel-coated filters.
- Evaluation of tumor development and vascularization in vivo after subcutaneous injection into nude mice.
- Analysis of blood vessel sprouting using the rat aortic ring assay.
- Measurement of VEGF expression levels.
Main Results:
- MT1-MMP overexpression enabled MCF7 cells to activate pro-MMP-2.
- Enhanced in vitro invasiveness was observed, irrespective of MMP-2 co-expression.
- MT1-MMP-expressing cells rapidly formed highly vascularized tumors in vivo.
- MT1-MMP promoted blood vessel sprouting and was associated with increased VEGF expression, indicating an angiogenic phenotype.
Conclusions:
- MT1-MMP overexpression significantly promotes tumor angiogenesis and invasiveness in breast cancer cells.
- The pro-angiogenic effects of MT1-MMP are largely independent of tumor cell-derived MMP-2.
- MT1-MMP is a key factor in tumor vascularization, suggesting its potential as a therapeutic target for anti-angiogenic strategies.