Abstract
The extracellular matrix (ECM) is a source of bioactive fragments called matricryptins or matrikines resulting from the proteolytic cleavage of extracellular proteins (e.g., collagens, elastin, and laminins) and proteoglycans (e.g., perlecan). Matrix metalloproteinases (MMPs), cathepsins, and bone-morphogenetic protein-1 release fragments, which regulate physiopathological processes including tumor growth, metastasis, and angiogenesis, a pre-requisite for tumor growth. A number of matricryptins, and/or synthetic peptides derived from them, are currently investigated as potential anti-cancer drugs both in vitro and in animal models. Modifications aiming at improving their efficiency and their delivery to their target cells are studied. However, their use as drugs is not straightforward. The biological activities of these fragments are mediated by several receptor families. Several matricryptins may bind to the same matricellular receptor, and a single matricryptin may bind to two different receptors belonging or not to the same family such as integrins and growth factor receptors. Furthermore, some matricryptins interact with each other, integrins and growth factor receptors crosstalk and a signaling pathway may be regulated by several matricryptins. This forms an intricate 3D interaction network at the surface of tumor and endothelial cells, which is tightly associated with other cell-surface associated molecules such as heparan sulfate, caveolin, and nucleolin. Deciphering the molecular mechanisms underlying the behavior of this network is required in order to optimize the development of matricryptins as anti-cancer agents.
Highlights
Matricryptins are biologically active fragments released from extracellular matrix (ECM) proteins and glycosaminoglycans by proteases (Davis et al, 2000)
We have extended the definition of matricryptins to the ectodomains of membrane collagens and membrane proteoglycans, which are released in the ECM by sheddases, and to fragments of ECM-associated enzymes such as Abbreviations: ECM, extracellular matrix; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; HA, hyaluronan; MAPK, mitogen-associated protein kinase; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; Receptor for HA-Mediated Motility (RHAMM), receptor for hyaluronic acid-mediated motility; TLR, toll-like receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor
Matricryptins and their Receptors lysyl oxidase, which initiates the covalent cross-linking of collagens and elastin, and matrix metalloproteinases (MMPs), which contribute to ECM remodeling (Ricard-Blum and Salza, 2014; Ricard-Blum and Vallet, 2015)
Summary
Matricryptins are biologically active fragments released from extracellular matrix (ECM) proteins and glycosaminoglycans by proteases (Davis et al, 2000). Endostatin and endorepellin, a matricryptin of perlecan, induce autophagy of endothelial cells, the autophagic activity of endorepellin being mediated by a VEGFR2-dependent pathway (Nguyen et al, 2009; Poluzzi et al, 2014).
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