Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading.
Proteoglycans located in basement membranes, the nanostructures underling epithelial and endothelial layers, are unique in several respects. They are usually large, elongated molecules with a collage of domains that share structural and functional homology with numerous extracellular matrix proteins, growth factors and surface receptors. They mainly carry heparan sulfate side chains and these contribute not only to storing and preserving the biological activity of various heparan sulfate-binding cytokines and growth factors, but also in presenting them in a more “active configuration” to their cognate receptors. Abnormal expression or deregulated function of these proteoglycans affect cancer and angiogenesis, and are critical for the evolution of the tumor microenvironment. This review will focus on the functional roles of the major heparan sulfate proteoglycans from basement membrane zones: perlecan, agrin and collagen XVIII, and on their roles in modulating cancer growth and angiogenesis.
Although a host of intracellular signals is known to contribute to wound healing, the role of the cell microenvironment in tissue repair remains elusive. Here we employed 2 different mouse models of genetic skin fragility to assess the role of the basement membrane protein collagen VII (COL7A1) in wound healing. COL7A1 secures the attachment of the epidermis to the dermis, and its mutations cause a human skin fragility disorder coined recessive dystrophic epidermolysis bullosa (RDEB) that is associated with a constant wound burden. We show that COL7A1 is instrumental for skin wound closure by 2 interconnected mechanisms. First, COL7A1 was required for re-epithelialization through organization of laminin-332 at the dermal-epidermal junction. Its loss perturbs laminin-332 organization during wound healing, which in turn abrogates strictly polarized expression of integrin α6β4 in basal keratinocytes and negatively impacts the laminin-332/integrin α6β4 signaling axis guiding keratinocyte migration. Second, COL7A1 supported dermal fibroblast migration and regulates their cytokine production in the granulation tissue. These findings, which were validated in human wounds, identify COL7A1 as a critical player in physiological wound healing in humans and mice and may facilitate development of therapeutic strategies not only for RDEB, but also for other chronic wounds.
Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms.
The members of the laminin family of heterotrimers are major constituents of all basement membranes, sheet-like extracellular structures, present in almost all organs. The laminins bind to cell surface receptors and thereby tightly connect the basement membrane to the adjacent cell layer. This provides for the specific basement membrane functions to stabilize cellular structures, to serve as effective physical barriers, and furthermore, to govern cell fate by inducing intracellular signalling cascades. Many different types of diseases involve basement membranes and laminins. Metastasizing solid tumors must pass through basement membranes to reach the vascular system, and various microbes and viruses enter the cells through direct interaction with laminins. Furthermore, whereas mutations in one specific laminin chain lead to a muscular disorder, mutations of other laminin chains cause skin blistering and kidney defects, respectively. This review summarizes recent progress concerning the molecular mechanisms of laminins in development and disease. The current knowledge may lead to clinical treatment of lamininopathies and may include stem-cell approaches as well as gene therapy.
Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the ␣21 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the ␣2 I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of ␣21. Microvascular endothelial cells from ␣21 ؊/؊ mice, but not those isolated from either wild-type or ␣11 ؊/؊ mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in ␣21 ؊/؊ mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin ␣21. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the ␣21 integrin receptor.The incorporation of new blood vessels into growing neoplasms is a prerequisite for tumor viability and progression. Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2-6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7). Endorepellin carries three laminin-like globular (LG) domains separated by epidermal growth factor-like repeats (8) and binds to numerous extracellular matrix proteins, growth factors, and receptors including collagen XVIII, fibulin-2, nidogen, fibroblast growth factor 7, fibroblast growth factor-binding protein, ECM1 (7, 9 -12), ␣-dystroglycan, and integrin ␣21 (9, 13-16). The endorepellin anti-angiogenic effect is parallel to several proteolytically released fragments from vascular basement membrane such as endostatin, the NC-1 domain of collagen type XVIII, and tumstatin, the NC-1 domain the of type IV collagen ␣3 chain (8,17,18). These fragments principally act on endothelial cells as "negative" ligands for specific integrin receptors. Endorepellin is a potent inhibitor in several angiogenesis assays such as endothelial cell migration, collagen-induced capillary morphogenesis, blood vessel recruitment into Matrigel plugs, and chicken chorioallontoic membrane (7,19). It also effectively retards in vivo tumor growth by specifically targeting tumor angiogenesis (20). We hypothesize that endorepellin takes effect via the LG3 domain binding to the integrin ␣21 causing actin disassembly and therefore affecting three key steps of angiogenesis: endothelial cell adhesion, migration, and morphogenesis.Here we have further investigated the endorepellin-␣21 integrin interactions by using cell-free experiments with a solub...
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