Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: A role for inflammatory cells in tumor invasion and angiogenesis

被引:286
作者
Shamamian, P
Schwartz, JD
Pocock, BJZ
Monea, S
Whiting, D
Marcus, SG
Mignatti, P
机构
[1] NYU, Sch Med, Dept Surg, SA Localio Lab Surg Res, New York, NY 10016 USA
[2] NYU, Sch Med, Kaplan Canc Ctr, New York, NY 10016 USA
[3] NYU, Sch Med, Vet Adm New York Harbor Healthcare Syst, New York, NY 10016 USA
[4] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
关键词
D O I
10.1002/jcp.10014
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Gelatinase A (MMP-2), a matrix metalloproteinase (MMP) involved in tumor invasion and angiogenesis, is secreted as an inactive zymogen (proMMP-2) and activated by proteolytic cleavage. Here we report that polymorphonuclear neutrophil (PMN)-derived elastase, cathepsin C, and proteinase-3 activate proMMP-2 through a mechanism that requires membrane-type I matrix metalloproteinase (MT1-MMP) expression. Immunoprecipitation of human PMN-conditioned medium with a mixture of antibodies to elastase, cathepsin G, and proteinase-3 abolished pro-MMP-2 activation, whereas individual antibodies were ineffective. Incubation of HT1080 cells with either purified PMN elastase or cathepsin G or proteinase-3 resulted in dose-and time-dependent proMMP-2 activation. Addition of PMN-conditioned medium to MT1-MMP expressing cells resulted in increased proMMP-2 activation and In vitro invasion of extracellular matrix (ECM), but had no effect with cells that express no MT1-MMP. MMP-2 activation by PMN-conditioned medium or purified elastase was blocked by the elastase inhibitor al-antitrypsin but not by Batimastat, an MMP inhibitor, showing that elastase activation of MMP-2 is not mediated by MMP activities. The PMN-conditioned medium-induced increase in cell invasion was blocked by Batimastat as well as by alpha (1)-antitrypsin, showing that PMN serine proteinases trigger a proteinase cascade that entails proMMP-2 activation: this gelatinase is the downstream effector of the proinvasive activity of PMN proteinases. These findings indicate a novel role for PMN-mediated inflammation in a variety of tissue remodeling processes including tumor invasion and angiogenesis. (C) 2001 Wiley-Liss, Inc.
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页码:197 / 206
页数:10
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