Context-dependent bioactivity of versican fragments

Abstract

Versican (VCAN) proteolysis and the accumulation of VCAN fragments occur in many developmental and disease processes, affecting extracellular matrix (ECM) structure and cell phenotype. Little is known about the significance of proteolysis and the roles of fragments, or how this ECM remodeling affects the microenvironment and phenotype of diseased cells. G1-DPEAAE fragments promote aspects of epithelial–mesenchymal transitioning in developing and diseased cells, resulting in cell migration. Enhanced proliferation and invasion of tumor and endothelial cells is directly associated with G1 domain deposition and G1-DPEAAE localization respectively. These tumorigenic and angiogenic roles could explain the disease exacerbating effect often associated with G1-containing fragments, however, the pathogenicity of G1 fragments depends entirely upon the context. Overall, VCAN fragments promote tumorigenesis and inflammation; however, the specific cleavage site, the extent of cleavage activity and the microenvironment in which cleavage occurs collectively determine how this pleiotropic molecule and its fragments influence cells.

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…In addition, a recent study (187) using bone marrow biopsies from 35 myeloma patients revealed a significant correlation of versikine accumulation with infiltration of CD8+ T cells supporting a model in which macrophages and regulatory DCs secrete tolerogenic versican which is subsequently degraded, generating versikine and further altering the immunosuppressive nature of the tumor microenvironment. Thus, taken together, these studies establish that both intact versican and a proteolytic degradation product of versican have immunomodulatory properties and suggest that the anti-tumor properties of versikine might antagonize the protumor properties of intact versican (13,23,73,75,188). The juxtaposition of these findings indicates that the consequences of ECM-derived-DAMP interactions with PRRs can have sharply differing outcomes depending on the contextual specifics of versican structure.…”

“…The degradation of versican is affected by several different families of proteases that increase during inflammation. Such proteases include matrix metalloproteinases (MMPs), i.e., MMP-1,−2,−3,−7, and−9 (64-66), serine protease plasmin (67), and at least five ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) MMPs, specifically ADAMTS-1,−4,−5,−9, and−20 [see reviews (12,13,(68)(69)(70)]. Cleavage of versican by ADAMTS-1,−4,−5, and−9 leads to production of an amino-terminal fragment, termed versikine, that can be detected using an antibody recognizing the neoepitope sequence DPEAAE (DPE) (12,71,72).…”

“…Cleavage of versican by ADAMTS-1,−4,−5, and−9 leads to production of an amino-terminal fragment, termed versikine, that can be detected using an antibody recognizing the neoepitope sequence DPEAAE (DPE) (12,71,72). Fragments such as versikine can act as DAMPs, interacting with immune and non-immune cells stimulating pro-and anti-inflammatory cytokine release and a modified immune response in both human and murine models (13,(73)(74)(75). Thus, many mechanisms are in place to regulate the expression and degradation of versican during the inflammatory process which ultimately influence key cellular events including cell adhesion, proliferation, migration, and ECM remodeling.…”

“…Leukocyte trafficking and localization are critical to events associated with the immune response. Specific components of the ECM can act as DAMPs or matrikines (11) promoting inflammatory cytokine synthesis and release by immune and non-immune cells (4,12,13). Proteoglycans, as components of the ECM, play a key part in providing intrinsic signals needed to coordinate critical events in the inflammatory cascade (4-6, 10, 14-23).…”

Versican: A Dynamic Regulator of the Extracellular Matrix

“…89 The examples are endostatin from type XVIII collagen, tumstatin from type IV collagen, and endorepellin from perlecan. 90 There are an increasing number of reports demonstrating the biological function of the N-terminal fragment of Vcan, 91 termed "versikine." Combined knockout mice of ADAMTS-5, ADAMTS-9, and ADAMTS-20 genes exhibit syndactyly due to impaired apoptosis by an accumulation of Vcan, and local treatment with versikine rescues the phenotype, indicating that versikine leads to cellular apoptosis.…”