Activation of tumor cell matrix metalloproteinase-2 by neutrophil proteinases requires expression of membrane-type 1 matrix metalloproteinase

J. D. Schwartz, Peter Shamamian, S. Monea, D. Whiting, S. G. Marcus, A. C. Galloway, P. Mignatti, G. B. Nackman

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background. Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. Methods. Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. Results. HT-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme form (72 kd). HT-1080 cells with high levels of MT1-MMP (HT-SE) secreted proMMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose- dependent generation of active, 62 kd MMP-2. In contrast, when PMN- conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. Conclusions. PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion.

Original languageEnglish (US)
Pages (from-to)232-238
Number of pages7
JournalSurgery
Volume124
Issue number2
DOIs
StatePublished - 1998
Externally publishedYes

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Matrix Metalloproteinase 14
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Neutrophils
Peptide Hydrolases
Membranes
Conditioned Culture Medium
Neoplasms
Enzyme Precursors
Secreted Matrix Metalloproteinases
Complementary DNA
Clone Cells
Serine Proteases
Gelatin
Extracellular Matrix
Enzymes
Serum

ASJC Scopus subject areas

  • Surgery

Cite this

Activation of tumor cell matrix metalloproteinase-2 by neutrophil proteinases requires expression of membrane-type 1 matrix metalloproteinase. / Schwartz, J. D.; Shamamian, Peter; Monea, S.; Whiting, D.; Marcus, S. G.; Galloway, A. C.; Mignatti, P.; Nackman, G. B.

In: Surgery, Vol. 124, No. 2, 1998, p. 232-238.

Research output: Contribution to journalArticle

Schwartz, J. D. ; Shamamian, Peter ; Monea, S. ; Whiting, D. ; Marcus, S. G. ; Galloway, A. C. ; Mignatti, P. ; Nackman, G. B. / Activation of tumor cell matrix metalloproteinase-2 by neutrophil proteinases requires expression of membrane-type 1 matrix metalloproteinase. In: Surgery. 1998 ; Vol. 124, No. 2. pp. 232-238.
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abstract = "Background. Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. Methods. Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. Results. HT-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme form (72 kd). HT-1080 cells with high levels of MT1-MMP (HT-SE) secreted proMMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose- dependent generation of active, 62 kd MMP-2. In contrast, when PMN- conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. Conclusions. PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion.",
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T1 - Activation of tumor cell matrix metalloproteinase-2 by neutrophil proteinases requires expression of membrane-type 1 matrix metalloproteinase

AU - Schwartz, J. D.

AU - Shamamian, Peter

AU - Monea, S.

AU - Whiting, D.

AU - Marcus, S. G.

AU - Galloway, A. C.

AU - Mignatti, P.

AU - Nackman, G. B.

PY - 1998

Y1 - 1998

N2 - Background. Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. Methods. Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. Results. HT-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme form (72 kd). HT-1080 cells with high levels of MT1-MMP (HT-SE) secreted proMMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose- dependent generation of active, 62 kd MMP-2. In contrast, when PMN- conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. Conclusions. PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion.

AB - Background. Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. Methods. Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. Results. HT-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme form (72 kd). HT-1080 cells with high levels of MT1-MMP (HT-SE) secreted proMMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose- dependent generation of active, 62 kd MMP-2. In contrast, when PMN- conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. Conclusions. PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion.

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