Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices

Exp Cell Res. 2001 Oct 15;270(1):110-8. doi: 10.1006/excr.2001.5306.


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.

MeSH terms

  • Animals
  • Cell Movement / physiology*
  • Collagen
  • Humans
  • Matrix Metalloproteinase 1 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinases, Membrane-Associated
  • Melanoma / physiopathology*
  • Metalloendopeptidases / biosynthesis
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Tissue Inhibitor of Metalloproteinase-2 / biosynthesis
  • Tumor Cells, Cultured


  • Tissue Inhibitor of Metalloproteinase-2
  • Collagen
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1