Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization.
Membrane-type metalloproteinase-1 (MT1-MMP) is a transmembrane metalloproteinase overexpressed in tumors, which plays a major role in the first step of pro-MMP-2 activation, leading to the generation of an intermediate 62 kDa species. The second step of MMP-2 activation that yields to the mature form is less understood and could involve an autocatalytic process and/or the activity of the plasminogen/plasmin system. Human melanoma A2058 cells, which express MMP-2 only in its pro-form, were used to determine the role of MT1-MMP during pericellular proteolysis and tumor progression. The induction of MT1-MMP overexpression by MT1-MMP cDNA transfection initiated the first step of MMP-2 activation. We provide evidence that a cooperation between the plasminogen/plasmin system and MT1-MMP endowed the cells with the ability to fully activate MMP-2 and with enhanced invasive properties in vitro. When injected subcutaneously in nude mice, MT1-MMP expressing clones induced rapid tumor growth and high tumor vascularization, while the control clones were poorly or not tumorigenic. Our data provide the first demonstration, in an experimental model, that MT1-MMP expression by tumor cells promotes tumor vascularization.
Sounni
Nor Eddine
NE
Laboratory of Tumor and Development Biology, University of Liège, CHU, Liège, Belgium.
Baramova
Eugenia N
EN
Munaut
Carine
C
Maquoi
Erik
E
Frankenne
Francis
F
Foidart
Jean-Michel
JM
Noël
Agnès
A
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008545:Melanoma / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009389:Neovascularization, Pathologic / Q000209:etiology; D010958:Plasminogen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C507096:Mmp14 protein, mouse; D010958:Plasminogen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14