The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia.

Matrix metalloproteinases (MMPs) are important for the pathogenesis and progression of different tumours. MMPs-2 and -9 are the principal MMPs produced by lymphocytes; these enzymes can degrade a number of matrix proteins but are the two main MMPs that digest type IV collagen, the major component of basement membranes. Therefore, these enzymes are potentially important for tissue invasion and remodelling by malignant lymphocytes. This study showed that chronic lymphocytic leukaemia (CLL) cells produce and secrete variable amounts of pro-MMP-9, but no MMP-2 or tissue inhibitor of metalloproteinase 1 (TIMP-1). The pro-enzyme was found in monomeric and dimeric forms and also complexed with lipocalin. Moreover, a small fraction of secreted monomer became associated with the cell surface and activated upon cell adhesion to insolubilized type IV collagen. High levels of intracellular MMP-9 were associated with advanced (stage C) disease and with poor patient survival. Immunohistochemical studies demonstrated that MMP-9 was associated with areas of tissue invasion and remodelling. The relatively specific MMP-9 inhibitors, Ro31-9790 (3 micromol/l) and TIMP-1, reduced CLL-cell migration through type IV collagen and through endothelial monolayers suggesting that the enzyme may also be important in malignant cell entry and egress to and from involved tissue. Our data raise the possibility that MMP-9 modulation may have therapeutic potential in advanced CLL.