The gelatinases MMP-2 and -9 show gelatin-binding repeats that resemble the collagen-binding type II motif of fibronectin (FN). MMP-23 also contains the unique cysteine array (CA) and an immunoglobulin (Ig)-like domain. Besides their differential domain structure, MMPs can be principally divided into secreted (MMP-1, -2, -3, -7, -8, -9, -10, -11, -12, -13, -19, -20, -21, -22, -27, -28) and membrane-anchored proteinases (MMP-14, -15, -16, -17, -23, -24, -25), the latter of which use either a transmembrane domain (TM) with a cytoplasmic domain (Cy) attached to it, a glycosylphosphatidylinositol (GPI) anchor, or an amino-terminal signal anchor (SA), which is only the case for MMP-23, as it is anchored in the plasma membrane. In addition to the minimal domain, most MMPs possess a hemopexin-like region, a domain composed of four repeats that resemble hemopexin and contain a disulfide bond (S-S) between the first and the last subdomain, which is linked to the catalytic domain via a flexible hinge region. Activation of the zymogen is often mediated by intracellular furin-like proteinases that target the furin recognition motif (Fu) between the pro-domain and the catalytic domain. Interaction of the -SH group of the pro-domain with the zinc ion of the catalytic domain keeps the enzyme as an inactive zymogen. All MMPs have the “minimal domain” in common, which contains three principal regions: an amino-terminal signal sequence (Pre) to be cleaved by the signal peptidase during entry into the endoplasmic reticulum, a pro-domain (Pro) containing a thiol-group (-SH) and a furin cleavage site, and the catalytic domain with a zinc-binding site (Zn 2+). (A) Matrix metalloproteinases (MMPs) are comprised of different subdomains. MMP Composition and Expression in the Stroma The pro-domain contains a consensus sequence and requires proteolytic cleavage by convertases, which, depending on the sequences, occurs intracellularly by furin or extracellularly by other MMPs or serine proteinases such as plasmin ( Sternlicht and Werb, 2001). Only after disruption of this interaction by a mechanism called cysteine switch, which is usually mediated by proteolytic removal of the pro-domain or chemical modification of the cysteine residue, does the enzyme become proteolytically active.
MMPs are initially expressed in an enzymatically inactive state due to the interaction of a cysteine residue of the pro-domain with the zinc ion of the catalytic site. The general structural blueprint of MMPs shows three domains that are common to almost all MMPs, the pro-peptide, the catalytic domain, and the hemopexin-like C-terminal domain that is linked to the catalytic domain via a flexible hinge region ( Figure 1A). The 23 MMPs expressed in humans are categorized by their architectural features. They play a crucial role in various physiological processes including tissue remodeling and organ development ( Page-McCaw et al., 2007), in the regulation of inflammatory processes ( Parks et al., 2004), and in diseases such as cancer ( Egeblad and Werb, 2002). MMPs are a family of zinc-dependent endopeptidases first described almost half a century ago ( Gross and Lapiere, 1962). Regarding the failure of MMP inhibitors as targets for anticancer therapy in clinical trials, we critically discuss the new insights into the functions of these extracellular proteinases in cancer, which, depending on the circumstances, may either suppress or promote tumorigenesis, or even act independently of their proteolytic activity. Here, we review the recent advances in our understanding of MMP-driven regulation of the tumor microenvironment. These enzymes regulate a variety of physiological processes and signaling events, and thus they represent key players in the molecular communication between tumor and stroma. Mounting evidence supports the view that extracellular proteinases, such as the matrix metalloproteinases (MMPs), mediate many of the changes in the microenvironment during tumor progression. Understanding the molecular mechanisms of this complex interplay between malignant cancer cells and the surrounding nonmalignant stroma represents one of the major challenges in cancer research. The milieu of the tumor microenvironment is akin to the inflammatory response in a healing wound, which promotes angiogenesis, turnover of the extracellular matrix (ECM), and tumor cell motility ( Coussens and Werb, 2002).
The resulting tumors are complex structures of malignant cancer cells embedded in vasculature and surrounded by a dynamic tumor stroma consisting of various nonmalignant cells, such as fibroblasts and myeloid cells. Cancer originates from mutations in genes that regulate essential pathways of cell function leading to uncontrolled outgrowth of tissue cells ( Hanahan and Weinberg, 2000).
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