Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices.
During melanoma progression, migrating cells must cross human dermis, a type I collagen-rich tissue. We have show that MMP-1 and MMP-2 act in a cumulative manner in the in vitro invasion of a three-dimensional type I collagen matrix by melanoma cells. Two melanoma cell lines (M1Dor and M3Da) previously reported to secrete proMMP-2 in a direct relationship with their tumorigenic potential into nude mice were used (F. Capon et al., 1999, Clin. Exp. Metastasis 17, 463-469). The highly tumorigenic cell line (M3Da) displayed a five-fold faster migration rate in type I collagen matrix, compared to its lower tumorigenic counterpart (M1Dor). In parallel, activation of proMMP-2 was evidenced in M3Da- but not M1Dor-populated collagen lattices. Such enzyme activation was associated with a significant decrease in TIMP-2 and TIMP-1 production. Agents known to interfere with proMMP-2 activation, i.e., excess TIMP-2, furin convertase inhibitor, and alphavbeta3 blocking antibody, reduced by 30-40% the type I collagen invasive capacity of M3Da cells. By comparison, batimastat, a wide-spectrum MMP inhibitor, exhibited a more pronounced inhibitory effect (>70%). It suggested that other collagenases than MMP-2 could participate in type I collagen invasion. Collagenase-3 (MMP-13) was produced at low levels by melanoma cells whatever the cell culture conditions. In contrast, M3Da and M1Dor cells secreted collagenase-1 (MMP-1) following 48 h of culture on plastic dishes. Growing melanoma cells in type I collagen gel did not modify enzyme production, but induced proMMP-1 activation in M3Da but not M1Dor cell-populated lattices. Blocking the plasmin-mediated proMMP-1 activation by aprotinin inhibited type I collagen gel invasion by 30%. Since the combination of aprotinin and furin convertase inhibitor reduced collagen invasiveness by melanoma cells to a level comparable to that attained with batimastat, we conclude that both MMP-2 and MMP-1 are involved in such tissue invasion.
Ntayi
C
C
Laboratoire de Recherche en Dermatologie, IFR-53 Biomolécules, Reims Cedex, 51095, France.
Lorimier
S
S
Berthier-Vergnes
O
O
Hornebeck
W
W
Bernard
P
P
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008545:Melanoma / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1