Matricryptins Network with Matricellular Receptors at the Surface of Endothelial and Tumor Cells

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.

New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart

“…6) In a broad sense, the fragments of ECM-associated enzymes (MMPs, a disintegrin and metalloproteinases and lysyl oxidase) and ECM-affiliated proteins (e.g., mucins, galectins and semaphorins) are also considered as matricryptins. [7][8][9] Because most matricryptins have been clarified to be an endogenous anti-angiogenic and/or anti-tumor factor, they are expected to be novel anti-tumor drugs and are thus being widely investigated. 10) Matricryptins also regulate fibrosis, wound-healing, inflammation and vasocontractility, and are considered to be associated with various diseases, such as cancer, arthritis, pulmonary and kidney disease.…”

Framing cancer progression: influence of the organ‐ and tumour‐specific matrisome

“…Several of them can inhibit angiogenesis by modulating endothelial cell proliferation (e.g., anastellin derived from fibronectin, endostatin from collagen type XVIII), apoptosis (e.g., arresten from collagen IV) or autophagy (endostatin and endoreppelin from perlecan). Others also can affect either cancer cell migration (arresten) or proliferation (endostatin) .…”

Gene delivery nanoparticles to modulate angiogenesis

“…In addition to its structural role, the proteolytic degradation of the vBM generates various bioactive fragments called matricryptins to regulate endothelial cell proliferation, migration, and survival as well as to help limit excessive angiogenesis during wound healing, inflammation, and disease processes. Several extracellular matrix (ECM) components can contribute to the generation of these fragments, notably, collagens IV (arresten; canstatin; tumstatin) and XVIII (endostatin) and heparan sulfates (endorepellin) [157]. …”

“…In humans, this activity is catalyzed by a tightly regulated family of 23 zinc-dependent endopeptidases known as matrix metalloproteinases (MMPs) which are secreted in response to growth factor signaling and are essential for initiating the process of angiogenesis (reviewed in [6]). MMP pro-angiogenic functions are controlled by the generation of anti-angiogenic matricryptins (described above) as well as endogenous inhibitors of MMP activity in the form of TIMPs [157, 181]. TIMPs are a family of four proteins (TIMP 1–4; 20–29 kDa) that bind to active sites of MMPs and inhibit their proteolytic activities.…”