Type IV collagen induces matrix metalloproteinase 2 activation in HT1080 fibrosarcoma cells.
Matrix metalloproteinase 2 (MMP-2) activation has been described as a "master switch" which triggers tumor spread and metastatic progression. We show here that type IV collagen, a major component of basement membranes, promotes MMP-2 activation by HT1080 cells. When plated on plastic, HT1080 cells constitutively processed the 66-kDa pro-MMP-2 into a 62-kDa intermediate activated form, most probably through a membrane type (MT) 1 MMP-dependent mechanism. In the presence of type IV collagen, part of this intermediate form was further processed to fully activated 59-kDa MMP-2. This activation was prevented by tissue inhibitor of MMP (TIMP)-2 and a broad-spectrum hydroxamic acid-based synthetic MMP inhibitor (GI129471). Type IV collagen-mediated pro-MMP-2 activation did not involve either a transcriptional modulation of MMP-2, MT1-MMP, or TIMP-2 expression nor any alteration of MT1-MMP protein synthesis or processing. An inverse relationship between MMP-2 activation and the concentration of secreted TIMP-2 was observed. This is consistent with our previous report that TIMP-2 degradation is probably linked to the MT1-MMP-dependent MMP-2 activation mechanism. Because invasive tumor cells must breach basement membranes at different steps of the metastatic dissemination, the ability of HT1080 cells to activate pro-MMP-2 in the presence of type IV collagen might represent a key regulatory mechanism for the acquisition of an invasive potential.
Maquoi
E
E
Laboratoire de Biologie des Tumeurs et du Développement, Université de Liège, Tour de Pathologie (B23), Liège, B-4000, Belgium.
Frankenne
F
F
Noël
A
A
Krell
H W
HW
Grams
F
F
Foidart
J M
JM
D003094:Collagen / Q000494:pharmacology*; D003208:Concanavalin A / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000032:analysis; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005354:Fibrosarcoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D061965:Matrix Metalloproteinase Inhibitors; D011498:Protein Precursors; D012333:RNA, Messenger; D003208:Concanavalin A; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D013755:Tetradecanoylphorbol Acetate