MTI-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

Membrane- type 1 matrix metalloproteinase ( MTI- 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 MTI is a critical mediator of invasive behaviour for this tumour type. Our results indicated that only those cell lines that expressed MTI were capable of penetrating a type I collagen barrier, with the capacity for both matrix degradation and invasion reflecting endogenous MTIexpression level. Ectopic MTI expression endowed an invasive phenotype upon cell lines lacking MTI 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 MTI, yet was minimally affected when other ( secreted) MMPs were inhibited using TIMP-I and the gelatinase inhibitor SB- 3CT. Whereas collagen I degradation was strikingly accelerated by ectopic MTI expression, cell motility remained unchanged. We conclude that MTI 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.