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

J Cell Physiol. 2001 Nov;189(2):197-206. doi: 10.1002/jcp.10014.


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 G, and proteinase-3 activate proMMP-2 through a mechanism that requires membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Immunoprecipitation of human PMN-conditioned medium with a mixture of antibodies to elastase, cathepsin G, and proteinase-3 abolished proMMP-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 alpha(1)-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cathepsin G
  • Cathepsins / pharmacology
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Enzyme Activation
  • Enzyme Precursors / metabolism*
  • Gelatinases / metabolism*
  • Humans
  • Leukocyte Elastase / pharmacology
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Metalloendopeptidases / physiology
  • Models, Biological
  • Myeloblastin
  • Neoplasm Invasiveness*
  • Neovascularization, Pathologic*
  • Neutrophils / enzymology*
  • Neutrophils / physiology*
  • Serine Endopeptidases / pharmacology*
  • Tumor Cells, Cultured


  • Culture Media, Conditioned
  • Enzyme Precursors
  • Cathepsins
  • Serine Endopeptidases
  • CTSG protein, human
  • Cathepsin G
  • Leukocyte Elastase
  • Myeloblastin
  • Gelatinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • progelatinase