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Matrix metalloproteinases generate angiostatin: effects on neovascularization
L A Cornelius1, L C Nehring, E Harding
1Division of Dermatology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA. lcorneli@imgate.wustl.edu
Journal of Immunology (Baltimore, Md. : 1950)
|December 23, 1998
Summary
Matrix metalloproteinases, particularly macrophage elastase (MME), generate angiostatin from plasminogen. This angiostatin effectively inhibits human microvascular endothelial cell proliferation, crucial for tumor growth.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Angiostatin, derived from plasminogen, inhibits endothelial cell proliferation and tumor metastasis.
- Tumor-associated macrophages producing elastolytic metalloproteinases are linked to angiostatin production in Lewis lung carcinoma models.
Purpose of the Study:
- To investigate the role of matrix metalloproteinases (MMPs) in generating biologically functional angiostatin from plasminogen.
- To determine the specific MMPs involved and their efficiency in angiostatin production.
- To confirm the requirement of macrophage elastase (MME) for MME-dependent angiostatin generation and its anti-proliferative effects on endothelial cells.
Main Methods:
- Purified murine and human MMPs were used to treat plasminogen.
- Catalytic efficiency of various MMPs (MME, gelatinases, stomelysins, interstitial collagenases) in generating angiostatin was assessed.
- Recombinant angiostatin and MME-generated angiostatin were tested for their effects on human microvascular endothelial cell proliferation and differentiation in vitro.
- Macrophages from MME-deficient and wild-type mice were utilized to evaluate MME's role in angiostatin generation.
Main Results:
- Purified MMPs efficiently generated biologically functional angiostatin from plasminogen.
- Macrophage elastase (MMP-12 or MME) was the most efficient MMP in producing angiostatin, followed by gelatinases and stomelysins.
- Interstitial collagenases showed minimal capacity for angiostatin generation.
- Both recombinant angiostatin and MME-generated angiostatin inhibited human microvascular endothelial cell proliferation and differentiation.
- MME was essential for generating angiostatin that inhibited endothelial cell proliferation in macrophages from MME-deficient mice.
Conclusions:
- Matrix metalloproteinases, especially MME, are key enzymes for generating angiostatin from plasminogen.
- The generated angiostatin possesses anti-angiogenic properties by inhibiting endothelial cell proliferation and differentiation.
- MME plays a critical role in the production of functional angiostatin, highlighting its potential significance in cancer therapy.