Neutrophil-derived serine proteinases enhance membrane type-1 matrix metalloproteinase-dependent tumor cell invasion.

Abstract

BACKGROUND:

Matrix metalloproteinase-2 degrades a variety of basement membrane components and is essential for tumor invasion. We have previously reported that membrane type-1 matrix metalloproteinase (MT1-MMP) cooperates with neutrophil-derived serine proteinases (NDPs; elastase, cathepsin G, protease-3) to activate matrix metalloproteinase-2. We therefore hypothesized that NDPs enhance tumor-cell invasion.

METHODS:

Clones of human HT1080 fibrosarcoma cells transfected with MT1-MMP sense (HT-SE) or antisense CDNA (HT-AS) were used. These cells express either high (HT-SE) or extremely low levels (HT-AS) of MT1-MMP relative to nontransfected HT1080 cells (HT-WT). The cells were incubated in the presence or absence of purified NDP, with or without alpha 1-antitrypsin or the MMP inhibitor batimastat. Cell invasion was measured with the use of Boyden chambers with polycarbonate membranes coated with a reconstituted extracellular matrix.

RESULTS:

Under control conditions HT-WT and HT-SE cells were 4-fold more invasive than HT-AS cells. The addition of NDP increased HT-WT and HT-SE cell invasion 60% to 100% but had no effect on HT-AS cells. alpha 1-antitrypsin or batimastat did not decrease the baseline invasiveness of HT-WT and HT-SE cells; however, they abrogated the stimulatory effect of NDP.

CONCLUSIONS:

HT1080 cell invasion depends on MT1-MMP expression. MT1-MMP overexpression does not increase invasiveness by itself. NDPs increase invasion by MT1-MMP expressing cells by activating matrix metalloproteinase-2.

• Authors: P Shamamian, B J Pocock, J D Schwartz, S Monea, N Chuang, D Whiting, S G Marcus, A C Galloway, P Mignatti
• Journal: Surgery (Surgery) Vol. 127 Issue 2 Pg. 142-7 (Feb 2000) ISSN: 0039-6060 [Print] United States
• PMID: 10686978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Culture Media, Conditioned
• Matrix Metalloproteinase Inhibitors
• Serine Proteinase Inhibitors
• Thiophenes
• alpha 1-Antitrypsin
• Phenylalanine
• batimastat
• Cathepsins
• Serine Endopeptidases
• CTSG protein, human
• Cathepsin G
• Pancreatic Elastase
• Myeloblastin
• Matrix Metalloproteinase 2

Topics

• Cathepsin G
• Cathepsins (physiology)
• Culture Media, Conditioned
• Fibrosarcoma (physiopathology)
• Humans
• Matrix Metalloproteinase 2 (physiology)
• Matrix Metalloproteinase Inhibitors
• Myeloblastin
• Neoplasm Invasiveness (physiopathology)
• Neutrophils (enzymology)
• Pancreatic Elastase (physiology)
• Phenylalanine (analogs & derivatives, pharmacology)
• Serine Endopeptidases (physiology)
• Serine Proteinase Inhibitors (pharmacology)
• Thiophenes (pharmacology)
• Tumor Cells, Cultured (physiology)
• alpha 1-Antitrypsin (pharmacology)