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Frontiers in Immunology 2020The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated... (Review)
Review
The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases.
Topics: Animals; Extracellular Matrix; Humans; Hyaluronic Acid; Inflammation; Leukocytes; Lipopolysaccharides; Lymphocyte Subsets; Mice; Models, Animal; Myeloid Cells; Rabbits; Rats; Receptors, Cell Surface; Stromal Cells; Toll-Like Receptors; Versicans
PubMed: 32265939
DOI: 10.3389/fimmu.2020.00512 -
Cancers Mar 2023-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer,...
-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human -mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that -mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene /IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.
PubMed: 36980752
DOI: 10.3390/cancers15061866 -
Matrix Biology : Journal of the... Jan 2019Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural... (Review)
Review
Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms.
Topics: Extracellular Matrix; Extracellular Matrix Proteins; Glycosaminoglycans; Heparan Sulfate Proteoglycans; Humans; Morphogenesis; Neoplasms; Neovascularization, Pathologic; Receptors, Cell Surface; Signal Transduction; Wound Healing
PubMed: 29128506
DOI: 10.1016/j.matbio.2017.10.008 -
Methods in Molecular Biology (Clifton,... 2015Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding...
Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding to its receptor CD44 and interactions of the versican C-terminal globular (G3) domain with a variety of extracellular matrix proteins, versican is a key component of well-defined networks in pericellular matrix and extracellular matrix. It is crucial for several developmental processes in the embryo and there is increasing interest in its roles in cancer and inflammation. Versican proteolysis by ADAMTS proteases is highly regulated, occurs at specific peptide bonds, and is relevant to several physiological and disease mechanisms. In this chapter, methods are described for the isolation and detection of intact and cleaved versican in tissues using morphologic and biochemical techniques. These, together with the methodologies for purification and analysis of recombinant versican and a versican fragment provided here, are likely to facilitate further progress on the biology of versican and its proteolysis.
Topics: Antibodies; Antigens; Cells, Cultured; Chromatography, Affinity; Humans; Hyaluronic Acid; Paraffin Embedding; Protein Isoforms; Protein Structure, Tertiary; Proteolysis; Reference Standards; Staining and Labeling; Versicans
PubMed: 25325983
DOI: 10.1007/978-1-4939-1714-3_46 -
Fukushima Journal of Medical Science Jan 2024Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports... (Review)
Review
Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports the tissue structure of organs such as the lungs, it has recently been reported that ECM has important biological activities for tissue morphogenesis, inflammation, wound healing, and tumor progression. Proteoglycans are the main constituent of ECM, with growing evidence that proteoglycans and their associated glycosaminoglycans play important roles in the pathogenesis of several diseases. However, their roles in the lungs are incompletely understood. Leukocyte migration into the lung is one of the main aspects involved in the pathogenesis of several lung diseases. Glycosaminoglycans bind to chemokines and their interaction fine-tunes leukocyte migration into the affected organs. This review focuses on the role chemokine and glycosaminoglycan interactions in neutrophil migration into the lung. Furthermore, this review presents the role of proteoglycans such as syndecan, versican, and hyaluronan in inflammatory and fibrotic lung diseases.
Topics: Humans; Lung; Extracellular Matrix; Glycosaminoglycans; Versicans; Lung Diseases
PubMed: 38267030
DOI: 10.5387/fms.2023-07 -
Seminars in Perinatology Mar 2023Progressive remodeling throughout the fetal and postnatal period is essential for anatomical closure of the ductus arteriosus (DA). Internal elastic lamina interruption... (Review)
Review
Progressive remodeling throughout the fetal and postnatal period is essential for anatomical closure of the ductus arteriosus (DA). Internal elastic lamina interruption and subendothelial region widening, elastic fiber formation impairment in the tunica media, and intimal thickening are distinctive features of the fetal DA. After birth, the DA undergoes further extracellular matrix-mediated remodeling. Based on the knowledge obtained from mouse models and human disease, recent studies revealed a molecular mechanism of DA remodeling. In this review, we focus on matrix remodeling and regulation of cell migration/proliferation associated with DA anatomical closure and discuss the role of prostaglandin E receptor 4 (EP4) signaling and jagged1-Notch signaling as well as myocardin, vimentin, and secretory components including tissue plasminogen activator, versican, lysyl oxidase, and bone morphogenetic proteins 9 and 10.
Topics: Animals; Mice; Humans; Ductus Arteriosus; Tissue Plasminogen Activator; Ductus Arteriosus, Patent; Extracellular Matrix; Signal Transduction
PubMed: 36906477
DOI: 10.1016/j.semperi.2023.151716 -
Glycobiology Mar 2015Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core... (Review)
Review
Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
Topics: Animals; Extracellular Matrix; Humans; Lung Diseases; Versicans
PubMed: 25371494
DOI: 10.1093/glycob/cwu120 -
EMBO Molecular Medicine Jan 2024Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations....
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1 aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.
Topics: Animals; Humans; Mice; Aortic Aneurysm, Thoracic; Aortic Diseases; Aortic Dissection; Azides; Deoxyglucose; Marfan Syndrome; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-akt; Versicans
PubMed: 38177536
DOI: 10.1038/s44321-023-00009-7 -
Cells Aug 2021The lung extracellular matrix (ECM) is a complex and dynamic mixture of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans...
The lung extracellular matrix (ECM) is a complex and dynamic mixture of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans (heparin, hyaluronic acid) and proteoglycans (perlecan, versican), that are essential for normal lung development and organ health [...].
Topics: Airway Remodeling; Animals; Cell Communication; Chronic Disease; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Lung; Lung Diseases
PubMed: 34440917
DOI: 10.3390/cells10082145