(A) Matrix metalloproteinases (MMPs) are comprised of different subdomains. 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 (Zn2+). Interaction of the -SH group of the pro-domain with the zinc ion of the catalytic domain keeps the enzyme as an inactive zymogen. 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. 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. 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. MMP-23 also contains the unique cysteine array (CA) and an immunoglobulin (Ig)-like domain. The gelatinases MMP-2 and -9 show gelatin-binding repeats that resemble the collagen-binding type II motif of fibronectin (FN).
(B) Expression pattern of proteinases and their physiological inhibitors in non-malignant stromal cells. Cells commonly found in the microenvironment of many cancers include inflammatory cells (such as neutrophils, macrophages, dendritic cells, lymphocytes, and mast cells), endothelial cells, fibroblasts, and hematopoietic progenitor cells. These cells express a plethora of proteinases that are released into the extracellular space and influence multiple events of tumor progression. Selected examples of proteinases and endogenous inhibitors expressed by these cell types are shown.