Expression Of Matrix Metalloproteinases And Their Tissue Inhibitors In Human Colorectal Cancer

BackgroundExtracellula.r matrix (ECM) is a dynamic reticular structure, which distributes among cell spaces. The structural proteins of ECM are varied and include collagens, proteoglycans,,multidomain glycoproteins and other biomacromolecules.These proteins can combine with the specific receptors which exist on the surface of cells. This will result in different gene expression by connecting with intracellular skeleton frame directly or initiating signal transduction cascades, and lead to cells proliferation and differentiation. Proteolytic degradation of ECM is critical event during many physiological and pathological conditions, including embryo morphogenesis, blastocyst implantation, angiogenesis, tissue reemodeling, tumor invasion and metastases. The initial steps of ECM degradation include degradation of cross-linked insoluble collagen and elastin fibers. The Matrix metalloproteinases(MMIPs),in particular the type 1V collagenase ,participate in the degradation of ECM components including the basement membrane(BM) ,which separates epithelia from stroma. M!vlPs and their tissue inhibitors (TJMPs) play an important role in the process of ECM destruction and remodeling. MMPs have been functionally defined as having the following characteristics: (1) they are proteinases that degrade at least one component of the extracellular matrix; (2) they contain a zinc ion and are inhibited by tissue inhibitors of metalloproteinases; (3) they are secreted in a latent form, requiring activation for proteolytic activity; (4) they are inhibited by tissue inhibitors of metalloproteinases; (5) they share common amino acid sequences . MMPs expression is regulated strictly by growth factors, cytokines, and hormones at transcription level, by their natural activators and inhibitors at protein level. Degradation of the ECM is associated with most physiological and pathologicalprocesses requiring tissue remodeling by the MMP superfamily. Five classes of MMPhave been identified so far based on their structure and/or substrate specificity includingcol1agenases, gelatinases, stromelysins, elastases, and membrane-typemetalloproteinases(MT-MMs). ALL MMPs display common tbatures, particularly therequirement of a proteolysis step to be activated. MMP-l' 9 can be activated by thefamily of serine proteinases as well as by other memb:rs of the WP family. Unlikeother MMPs,the activation of MMP-2(gelatinase A/72-kd type IV collagenase) takesplace at the ceIl surface, which confers to this unique metalIoproteinase a pivotal role in..migration and growth of tumor cells, a process requiring the 'remodeling of basementmembranes, the thin extracellular matrices that underlie epithelial, endothelial, and nervecells. A major breakihrough in the knowledge of MMP-2 activation process came fromthe recent discovery of MT-MMPs, the new class of MMPs sharing a tr8nsmembranedomain. MMP-2 activation is achieved only by MMPs with MT-MMP appearing to playan important role.It has been shown in vitro that MT1-MMP might be associated to thetissue inhibitor of metalloproteinase-2,both acting together as a recePtor for pro-MMP-2and leading to the cleavage of the Zymogen.M-2 is expressed in differellt type of human epithelial cancer, such as breast,ovarian, gastric.and colorectal cancer,and its level seems to be related to malignancy andinvasion.The activity of MMP-2 is modulated by TIMP-2, TIMP-2 bindsnoncovalently to the proform of the 72 kda tyPe IV collagenase and inhibitS itsenZyInatic activity, whereas TM-1 aPpears to inhibit most of the interstitialcollagenases and the 92 kda type IV collagenase. However, there have been severalreports that the level of MMP-2 is nOt relatCd to malignancy and invasion and that it isthe l...