MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells.
Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane metalloprotease that plays an important role in the invasion of many solid tumour types, promotes pericellular matrix degradation and may also stimulate tumour cell motility. As both these processes are key contributors to intraperitoneal ovarian tumour metastasis, we examined six ovarian cancer cell lines to determine whether MT1 is a critical mediator of invasive behaviour for this tumour type. Our results indicated that only those cell lines that expressed MT1 were capable of penetrating a type I collagen barrier, with the capacity for both matrix degradation and invasion reflecting endogenous MT1 expression level. Ectopic MT1 expression endowed an invasive phenotype upon cell lines lacking MT1 that were previously non-invasive, indicating the crucial role of this protease. Conversely, invasion was abolished by tissue inhibitor of metalloproteinase-2 (TIMP-2), a potent inhibitor of MT1, yet was minimally affected when other (secreted) MMPs were inhibited using TIMP-1 and the gelatinase inhibitor SB-3CT. Whereas collagen I degradation was strikingly accelerated by ectopic MT1 expression, cell motility remained unchanged. We conclude that MT1 is necessary for collagen I invasion by ovarian cancer cells, and that its requisite activity is the promotion of matrix degradation, with no impact on cell motility.
Sodek
K L
KL
Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, Canada.
Ringuette
M J
MJ
Brown
T J
TJ
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D024042:Collagen Type I; D053511:Matrix Metalloproteinase 14