Key Points
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Basement membrane (BM) proteoglycans are more than charged filtering agents. These complex macromolecules can direct cell responses by a wide range of sophisticated mechanisms. BM proteoglycans are directly involved in regulating angiogenesis and, consequently, tumour progression, and their partial or total absence causes several congenital diseases that affect the cardiovascular, musculoskeletal and nervous systems.
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Whereas the two heparan sulphate proteoglycans collagen XVIII and perlecan dictate BM stability and integrity in a variety of tissues, C-terminal-derived fragments of both collagen XVIII (endostatin) and perlecan (endorepellin) inhibit the growth of blood vessels by targeting tumour-associated endothelial cells. BM proteoglycans can have a bipolar activity — through the heparan sulphate chains they function as pro-angiogenic factors by modulating growth factor activity, whereas through their C-terminal angiostatic fragments they have the opposite function.
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The mechanism of action of endostatin and endorepellin involves their specific interaction with two cell surface receptors, the α5β1 and the α2β1 integrins, respectively, through a process that ultimately disrupts the endothelial cell cytoskeleton and focal adhesions, thereby blocking cell migration and capillary morphogenesis. This seems to be the primary angiostatic function of these processed forms of BM proteoglycans.
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The presence of these fragments in the urine and blood of normal and diseased patients indicate that they might exert a physiological role in vivo, and that, in the future, they could become biomolecular markers for certain diseases.
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A number of future challenges include the precise delineation of their signalling networks and an improved understanding of their in vivo activities and interacting partners. By increasing our knowledge we will optimize the use of these endogenous angiogenesis inhibitors in the battle against cancer and other diseases where angiogenesis is dominant.
Abstract
The biology of basement membrane proteoglycans extends far beyond the original notion of anionic filters. These complex molecules have dual roles as structural constituents of basement membranes and functional regulators of several growth-factor signalling pathways. As such, they are involved in angiogenesis and, consequently, in tumour progression and their partial or total absence causes several congenital defects that affect the musculoskeletal, cardiovascular and nervous systems. New findings indicate a potential functional coupling between the intricate make-up of basement membrane proteoglycans and their ability to control important biological processes.
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Acknowledgements
I thank C. C. Clark and J. Hassell for critical reading of this manuscript, G. Bix and C. C. Reed for help with the illustrations and valuable comments, K. Camphausen for generously providing Fig. 3 and ART (Advanced Research Technologies) Inc. for the help with computer imaging. I apologize for failing to cite all relevant studies in the field because of space constraints. The original research was supported in part by the National Institutes of Health, and by the Commonwealth of Pennsylvania.
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FURTHER INFORMATION
Glossary
- BASEMENT MEMBRANE
-
A thin, complex extracellular matrix that separates endothelial and epithelial cells from their subjacent connective tissues. It is composed of various collagens, proteoglycans and adhesive glycoproteins.
- HEPARAN SULPHATE PROTEOGLYCAN
-
A specialized protein that has the glycosaminoglycan heparan sulphate covalently attached to a serine residue within a region often enriched in acidic amino acid residues.
- MULTIPLEXINS
-
(Multiple triple helix domains and interruptions.) This collagen subfamily comprises types XV and XVIII, which contain several interruptions in the central triple-helical (Gly–X–Y motif) domain and a unique Cterminal (NC1) domain. The interruptions generate flexible regions that enable the formation of polymers different to those generated by the fibrillar collagen types I, II, III, V and XI.
- NEUROMUSCULAR JUNCTION
-
The site of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.
- BASEMENT MEMBRANE ZONE
-
A region contiguous with the basement membrane where various proteins function as the anchoring structures to the subjacent connective tissue.
- FIBROCARTILAGE
-
A specialized form of cartilage composed of bundles of thick, clearly-defined collagen fibres, which is found in symphyseal joints (such as vertebrae) and in intervertebral and articular discs. It withstands tension and pressure, and absorbs shocks.
- CHOROID PLEXI
-
Collections of villous-like processes at select sites in the ventricular system of the brain. These processes contain a special secretory epithelium that secretes cerebrospinal fluid.
- INTEGRINS
-
A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.
- GROWTH PLATE
-
An area of developing cartilaginous tissue near the ends of long bones, between the widened part of the shaft (the metaphysis) and the end (epiphysis) of the bone. The growth plate regulates and helps determine the length and shape of the mature bone.
- WNT PROTEINS
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A family of highly conserved, secreted signalling molecules that regulate cell–cell interactions during embryogenesis.
- MATRIX METALLOPROTEINASES (MMPs).
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A large family of secreted or transmembrane metal-dependent enzymes that collectively can digest all extracellular matrix and basement membrane constituents. They are active during tissue remodelling and angiogenesis.
- XENOGRAFT
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Tissue or organ graft between species. These grafts are usually rejected unless immunocompromised animals are used.
- LG
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(Laminin-like globular domain). LG modules are present in a number of basement membrane constituent proteins including laminin, perlecan and agrin. They fold into individual units and often possess important biological activity, as in the case of perlecan LG3.
- STRESS FIBRES
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Bundles of parallel filaments that contain F-actin and other contractile molecules. They often stretch between cell attachments as if under stress.
- COLLAGEN SANDWICH
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A widely used in vitro angiogenic assay in which endothelial cells are cultured between two layers of collagen type I. Within hours, visible capillary-like structures are formed.
- MATRIGEL
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The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and therefore resembles the basement membrane.
- LIPID RAFTS
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Rich in cholesterol, glycosphingolipids, glycosylphosphatidylinositol-anchored proteins and signalling molecules, these membrane microdomains function as signalling platforms.
- FOCAL ADHESION
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An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin signalling platform.
- I DOMAIN
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A ∼200 amino-acid inserted domain in the N-terminal region of the α2 and α1 integrin subunits that specifically binds various collagens. The binding is concentration-dependent and requires manganese and magnesium ions. The I domain is also known as MIDAS, for metal ion-dependent adhesion site.
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Iozzo, R. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6, 646–656 (2005). https://doi.org/10.1038/nrm1702
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DOI: https://doi.org/10.1038/nrm1702
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