Angiogenesis, the formation of new blood vessels from preexisting ones, is a key event in tumor progression controlled by a balance between positive and negative regulators (1, 2). From this observation has emerged the concept of the "angiogenic switch" in which endothelial activation status is determined by the induction of angiogenic factors and/or the loss of inhibitors (3). Positive regulators include at least vascular endothelial growth factor family (VEGF-A, -B, -C, -D), 1 fibroblast growth factors, placental-like growth factor (PlGF), angiopoietins, their tyrosine kinase receptors (VEGF-R1, -R2; Tie1 and Tie2) and neuropilin-1 (NRP-1), a co-receptor for VEGF (1, 4). An increasing number of negative regulators have been identified such as inhibitors of proteinases, thrombospondins, interferons, chemokines (IP-10 and PF-4), and bioactive fragments of the extracellular matrix (2, 4). Once a tumor has acquired an angiogenic phenotype, tumor cell migration, invasion, and vessel sprouting require the dynamic and coordinated action of many cell surface molecules, including proteinases and integrins mediating cell-matrix interactions.Among the cell-associated proteinases, matrix metalloproteinases (MMPs) anchored to the plasma membrane, called membrane-type MMPs (MT-MMPs) play a pivotal role in pericellular proteolysis. Of the six MT-MMPs that have been identified to date, four (MT1-, MT2-, MT3-, and MT5-MMP) contain a transmembrane domain followed by a cytoplasmic tail and two (MT4-and MT6-MMP) are tethered to the cell surface via a glycosylphosphatidylinositol link (for review, see . It now appears that all MT-MMPs may have the ability to activate pro-MMP2 (9 -13). Although, each of the four physiological tissue inhibitors of MMPs (TIMPs) can non selectively bind to all active MMPs, TIMP1 is unable to inhibit effectively MT1, 2, 3, and 5-MMPs (14). TIMP-2 has dual functions, inhibiting the activity of each MT-MMP and participating in the activation of pro-MMP2 through the formation of a ternary complex formed of MT1-MMP, TIMP-2, and pro-MMP2 (for review, see Refs. 7,15,and 16). MMP2 activation by MT1-MMP could be promoted by interaction with integrin (17) and oligomerization of 19).

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.Keywords: MT1-MMP ; tumoral angiogenesis ; vascular endothelial growth factor ; protease inhibitors ; estradiol MMP structure and functionsMatrix metalloproteinases (MMPs) are a broad family of zinc-binding endopeptidases that play a key role in the extracellular matrix (ECM) degradation associated with cancer cell invasion, metastasis and angiogenesis (Egeblad and Werb, 2002;McCawley and Matrisian, 2000). At present, more than 21 human MMPs and the homologues from other species have been identified (Egeblad and Werb, 2002). The MMP family can be segregated into two groups, the soluble type and the membrane-type MMPs (MT-MMPs and MMP23). Although initially classified according to their substrate specificity (McCawley and Matrisian, 2000), the MMP classification is now based on their structure (Egeblad and Werb, 2002). The 'minimal-domain MMPs' (MMP7 and MMP26) contains (i) a signal peptide that directs them to the endoplasmic reticulum, (ii) a propeptide, with a zinc-interacting thiol (SH) group that maintains the proMMP in a latent form (zymogen), and (iii) a catalytic domain containing the highly conserved Zn 2+ binding site (HEXGHXXGXXHS/T) (Fig. 1). With the exception of MMP23, all other MMPs display a prolinerich hinge region that links the catalytic domain to the hemopexin/vitronectin-like domain. This C-terminal domain influences substrate specificity and the binding to tissue inhibitors of MMPs (TIMPs) and cell surface molecules. The hemopexin-containing MMPs are further distinguished by the presence of specific insert(s). The gelatin-binding MMPs (MMP2 and MMP9 or gelatinases) contain inserts that resemble the collagen-binding type II repeats of fibronectin. The membrane type (MT)-MMPs have a single pass transmembrane domain and a short cytoplasmic...

No abstract

No abstract