Membrane Type I Matrix Metalloproteinase Usurps Tumor Growth Control Imposed by the Three-Dimensional Extracellular Matrix

Cell. 2003 Jul 11;114(1):33-45. doi: 10.1016/s0092-8674(03)00513-0.

Abstract

Cancer cells are able to proliferate at accelerated rates within the confines of a three-dimensional (3D) extracellular matrix (ECM) that is rich in type I collagen. The mechanisms used by tumor cells to circumvent endogenous antigrowth signals have yet to be clearly defined. We find that the matrix metalloproteinase, MT1-MMP, confers tumor cells with a distinct 3D growth advantage in vitro and in vivo. The replicative advantage conferred by MT1-MMP requires pericellular proteolysis of the ECM, as proliferation is fully suppressed when tumor cells are suspended in 3D gels of protease-resistant collagen. In the absence of proteolysis, tumor cells embedded in physiologically relevant ECM matrices are trapped in a compact, spherical configuration and unable to undergo changes in cell shape or cytoskeletal reorganization required for 3D growth. These observations identify MT1-MMP as a tumor-derived growth factor that regulates proliferation by controlling cell geometry within the confines of the 3D ECM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division / physiology*
  • Cell Size / physiology
  • Collagen Type I / metabolism
  • Collagen Type I / ultrastructure
  • Cytoskeleton / metabolism
  • Cytoskeleton / ultrastructure
  • Dogs
  • Extracellular Matrix / enzymology*
  • Extracellular Matrix / ultrastructure
  • Growth Substances / metabolism
  • Humans
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Microscopy, Electron
  • Neoplasm Invasiveness / physiopathology*
  • Neoplasms / enzymology*
  • Neoplasms / physiopathology
  • Repressor Proteins / metabolism
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / ultrastructure

Substances

  • Collagen Type I
  • Growth Substances
  • Repressor Proteins
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases