Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix.
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.
Hotary
Kevin B
KB
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Allen
Edward D
ED
Brooks
Peter C
PC
Datta
Nabanita S
NS
Long
Michael W
MW
Weiss
Stephen J
SJ
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D048429:Cell Size / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004285:Dogs; D005109:Extracellular Matrix / Q000201:enzymology* / Q000648:ultrastructure; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D008854:Microscopy, Electron; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009369:Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D012097:Repressor Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000648:ultrastructure
D024042:Collagen Type I; D006133:Growth Substances; D012097:Repressor Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases