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

• Published in: Surgery 2000-02, Vol.127 (2), p.142-147
• Main Authors: Shamamian, Peter, Pocock, Ben J.Z., Schwartz, Jess D., Monea, Sara, Chuang, Neal, Whiting, David, Marcus, Stuart G., Galloway, Aubrey C., Mignatti, Paolo
• Format: Article
• Language: English
• Subjects: alpha 1-Antitrypsin - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cathepsin G; Cathepsins - physiology; Culture Media, Conditioned; Fibrosarcoma - physiopathology; General aspects; Humans; Matrix Metalloproteinase 2 - physiology; Matrix Metalloproteinase Inhibitors; Medical sciences; Myeloblastin; Neoplasm Invasiveness - physiopathology; Neutrophils - enzymology; Pancreatic Elastase - physiology; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Serine Endopeptidases - physiology; Serine Proteinase Inhibitors - pharmacology; Thiophenes - pharmacology; Tumor Cells, Cultured - physiology; Tumors
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1067/msy.2000.101155

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 α1-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. α1-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. (Surgery 2000;126:142-7.)