Abstract
Spatial and temporal regulation of the pericellular proteolytic environment by local growth factors, such as EGF and TGF-β, initiates a wide repertoire of cellular responses coupled to a plasmin/matrix metalloproteinase (MMP) dependent stromal-remodeling axis. Cell motility and invasion, tumor metastasis, wound healing, and organ fibrosis, for example, represent diverse events controlled by expression of a subset of genes that encode various classes of tissue remodeling proteins. These include members of the serine protease and MMP families that functionally constitute a complex system of interacting protease cascades and titrated by their respective inhibitors. Several structural components of the extracellular matrix are upregulated by TGF-β as are matrix-active proteases (e.g., urokinase (uPA), plasmin, MMP-1, -3, -9, -10, -11, -13, -14). Stringent controls on serine protease/MMP expression and their topographic activity are essential for maintaining tissue homeostasis. Targeting individual elements in this highly interactive network may lead to novel therapeutic approaches for the treatment of cancer, fibrotic diseases, and chronic wounds.
Highlights
Epithelial transdifferentiation or cellular “plasticity” refers to a specialized morphogenetic switch typified by loss of normal epithelial properties, a gain in the expression of genes generally restricted to the mesenchymal lineage and conversion of sessile, nonmotile cells to a migratory phenotype [1, 2]
Stromal PAI-1 is itself a substrate for several extracellular proteases including elastase, MMP3 and plasmin resulting in the generation of rather specific PAI-1 cleavage products [32, 33, 51,52,53]
Such “cleaved” PAI-1 is unable to bind its target plasminogen activators uPA and tissue-type PA to inhibit plasmin-based proteolysis but retains the ability to bind to the low-density lipoprotein receptor-related protein-1 (LRP1) where it effectively augments cell migration through a uPA/tPA complexindependent interaction [54]
Summary
Epithelial transdifferentiation or cellular “plasticity” refers to a specialized morphogenetic switch typified by loss of normal epithelial properties, a gain in the expression of genes generally restricted to the mesenchymal lineage and conversion of sessile, nonmotile cells to a migratory phenotype [1, 2]. Biochemistry Research International carcinoma [18,19,20] During this transition, and despite increased autocrine/paracrine expression of TGF-β, cells often become refractory to the normally growth-suppressive effects of TGF-β family members due, in part, to downregulation of TGF-β receptors and/or anomalies in TGFβ-initiated signaling pathways [20, 21]. In tissue fibrotic disorders, differentiation, proliferation, and subsequent interstitial accumulation of “fibroblastoid” elements in the kidney and lung (two of the most well-studied organ systems in the context of fibroproliferative disease) appear to result from a programmed, but persistent, response to several profibrotic cytokines, the most prominent of which is TGF-β [11]
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