scholarly journals Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 455 ◽  
Author(s):  
Antonio Palumbo ◽  
Nathalia Meireles Da Costa ◽  
Bruno Pontes ◽  
Felipe Leite de Oliveira ◽  
Matheus Lohan Codeço ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Esophageal Cancer ◽  
Molecular Mechanisms ◽  
Dermatan Sulfate ◽  
Lysyl Oxidase ◽  
Wide Spectrum ◽  
Solid Base ◽  
Oncogenic Signaling ◽  
Ecm Remodeling ◽  
Esophageal Carcinogenesis

In the last years, the extracellular matrix (ECM) has been reported as playing a relevant role in esophageal cancer (EC) development, with this compartment being related to several aspects of EC genesis and progression. This sounds very interesting due to the complexity of this highly incident and lethal tumor, which takes the sixth position in mortality among all tumor types worldwide. The well-established increase in ECM stiffness, which is able to trigger mechanotransduction signaling, is capable of regulating several malignant behaviors by converting alteration in ECM mechanics into cytoplasmatic biochemical signals. In this sense, it has been shown that some molecules play a key role in these events, particularly the different collagen isoforms, as well as enzymes related to its turnover, such as lysyl oxidase (LOX) and matrix metalloproteinases (MMPs). In fact, MMPs are not only involved in ECM stiffness, but also in other events related to ECM homeostasis, which includes ECM remodeling. Therefore, the crucial role of distinct MMPs isoform has already been reported, especially MMP-2, -3, -7, and -9, along EC development, thus strongly associating these proteins with the control of important cellular events during tumor progression, particularly in the process of invasion during metastasis establishment. In addition, by distinct mechanisms, a vast diversity of glycoproteins and proteoglycans, such as laminin, fibronectin, tenascin C, galectin, dermatan sulfate, and hyaluronic acid exert remarkable effects in esophageal malignant cells due to the activation of oncogenic signaling pathways mainly involved in cytoskeleton alterations during adhesion and migration processes. Finally, the wide spectrum of interactions potentially mediated by ECM may represent a singular intervention scenario in esophageal carcinogenesis natural history and, due to the scarce knowledge on the cellular and molecular mechanisms involved in EC development, the growing body of evidence on ECM’s role along esophageal carcinogenesis might provide a solid base to improve its management in the future.

Lysyl oxidases: from enzyme activity to extracellular matrix cross-links

2019 ◽  
Vol 63 (3) ◽  
pp. 349-364 ◽  
Author(s):  
Sylvain D. Vallet ◽  
Sylvie Ricard-Blum
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Lysyl Oxidase ◽  
Dimensional Structure ◽  
Cross Linking ◽  
Copper Binding ◽  
Molecular Features ◽  
Ecm Proteins ◽  
Cross Links

Abstract The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase like proteins (LOXL1-4). They are copper amine oxidases with a highly conserved catalytic domain, a lysine tyrosylquinone cofactor, and a conserved copper-binding site. They catalyze the first step of the covalent cross-linking of the extracellular matrix (ECM) proteins collagens and elastin, which contribute to ECM stiffness and mechanical properties. The role of LOX and LOXL2 in fibrosis, tumorigenesis, and metastasis, including changes in their expression level and their regulation of cell signaling pathways, have been extensively reviewed, and both enzymes have been identified as therapeutic targets. We review here the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans, and by inhibitors. We also make an overview of the major ECM cross-links, because they are the ultimate molecular readouts of LOX/LOXL activity in tissues. The recent 3D model of LOX, which recapitulates its known structural and biochemical features, will be useful to decipher the molecular mechanisms of LOX interaction with its various substrates, and to design substrate-specific inhibitors, which are potential antifibrotic and antitumor drugs.

scholarly journals Genetic Susceptibility and Protein Expression of Extracellular Matrix Turnover-Related Genes in Oral Submucous Fibrosis

2020 ◽  
Vol 21 (21) ◽  
pp. 8104
Author(s):  
Ru-Hsiu Cheng ◽  
Yi-Ping Wang ◽  
Julia Yu-Fong Chang ◽  
Yu-Hwa Pan ◽  
Mei-Chi Chang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Oral Cancer ◽  
Genetic Susceptibility ◽  
Molecular Mechanisms ◽  
Lysyl Oxidase ◽  
Oral Submucous Fibrosis ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Contributing Factors ◽  
Plasminogen Activator Inhibitor 1 ◽  
Submucous Fibrosis

Betel quid (BQ) chewing increased the risk of oral cancer and oral submucous fibrosis (OSMF), an oral premalignant disorder (OPMD) with malignant transformation potential. BQ components such as areca nut (AN), trauma by coarse AN fiber, catechin, copper, alkaloids, stimulated reactive oxygen species (ROS), inflammation and cytotoxicity are suggested to be the contributing factors. They may induce tissue inflammation, proliferation of fibroblasts and collagen deposition, myofibroblast differentiation and contraction, collagen cross-links and inhibit collagen phagocytosis, finally leading to the development of OSMF and oral cancer. These events are mediated by BQ components-induced changes of extracellular matrix (ECM) turnover via regulation of TGF-β1, plasminogen activator inhibitor-1 (PAI-1), cystatin, lysyl oxidase (LOX) and tissue inhibitors of metalloproteinases (TIMPs) and metalloproteinases (MMPs). Genetic susceptibility is also involved in these disease processes. Further understanding the molecular mechanisms of BQ-induced OSMF and oral cancer can be helpful for future disease prevention and treatment.

scholarly journals Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart

2021 ◽  
Vol 128 (1) ◽  
pp. 24-38
Author(s):  
Ana Rubina Perestrelo ◽  
Ana Catarina Silva ◽  
Jorge Oliver-De La Cruz ◽  
Fabiana Martino ◽  
Vladimír Horváth ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Focal Adhesion ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Dynamics Simulation ◽  
Cell Homing ◽  
Ecm Remodeling ◽  
3 Dimensional ◽  
The Impact

Rationale: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. Objectives: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. Methods and Results: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFβ1 (transforming growth factor β1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. Conclusions: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

scholarly journals LOXL2—A New Target in Antifibrogenic Therapy?

2019 ◽  
Vol 20 (7) ◽  
pp. 1634 ◽  
Author(s):  
Angela Puente ◽  
Jose Fortea ◽  
Joaquin Cabezas ◽  
Maria Arias Loste ◽  
Paula Iruzubieta ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Liver Fibrosis ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Lysyl Oxidase ◽  
Portal Pressure ◽  
Induce Cell Cycle Arrest ◽  
Cell Functions ◽  
Extracellular Matrix Components ◽  
Matrix Components

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.

scholarly journals broad controls leg imaginal disc morphogenesis in Drosophila via regulation of cell shape changes and remodeling of extracellular matrix

2019 ◽  
Author(s):  
Clinton Rice ◽  
Stuart Macdonald ◽  
Xiaochen Wang ◽  
Robert E Ward
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Drosophila Melanogaster ◽  
Cell Shape ◽  
Imaginal Disc ◽  
Molecular Mechanisms ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Cell Shape Changes ◽  
Shape Changes

AbstractImaginal disc morphogenesis during metamorphosis in Drosophila melanogaster provides an excellent model to uncover molecular mechanisms by which hormonal signals effect physical changes during development. The broad (br) Z2 isoform encodes a transcription factor required for disc morphogenesis in response to 20-hydroxyecdysone, yet how it accomplishes this remains largely unknown. Here, we show that amorphic br5 mutant discs fail to remodel their basal extracellular matrix (ECM) after puparium formation and do not undergo necessary cell shape changes. RNA sequencing of wild type and mutant leg discs identified 717 genes differentially regulated by br; functional studies reveal that several are required for adult leg formation, particularly those involved in remodeling the ECM. Additionally, br Z2 expression is abruptly shut down at the onset of metamorphosis, and expressing it beyond this time results in failure of leg development during the late prepupal and pupal stages. Taken together, our results suggest that br Z2 is required to drive ECM remodeling, change cell shape, and maintain metabolic activity through the mid prepupal stage, but must be switched off to allow expression of pupation genes.Summary StatementThe Drosophila melanogaster ecdysone-responding transcription factor broad controls morphogenetic processes in leg imaginal discs during metamorphosis through regulation of genes involved in extracellular matrix remodeling, metabolism, and cell shape changes and rearrangements.

scholarly journals Healthy Subcutaneous and Omental Adipose Tissue Is Associated with High Expression of Extracellular Matrix Components

2022 ◽  
Vol 23 (1) ◽  
pp. 520
Author(s):  
Matúš Soták ◽  
Meenu Rohini Rajan ◽  
Madison Clark ◽  
Christina Biörserud ◽  
Ville Wallenius ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Lysyl Oxidase ◽  
Subcutaneous Fat ◽  
High Expression ◽  
Adipose Tissues ◽  
Ecm Remodeling ◽  
Omental Adipose Tissue ◽  
Extracellular Matrix Components ◽  
Metabolic Conditions

Obesity is associated with extensive expansion and remodeling of the adipose tissue architecture, including its microenvironment and extracellular matrix (ECM). Although obesity has been reported to induce adipose tissue fibrosis, the composition of the ECM under healthy physiological conditions has remained underexplored and debated. Here, we used a combination of three established techniques (picrosirius red staining, a colorimetric hydroxyproline assay, and sensitive gene expression measurements) to evaluate the status of the ECM in metabolically healthy lean (MHL) and metabolically unhealthy obese (MUO) subjects. We investigated ECM deposition in the two major human adipose tissues, namely the omental and subcutaneous depots. Biopsies were obtained from the same anatomic region of respective individuals. We found robust ECM deposition in MHL subjects, which correlated with high expression of collagens and enzymes involved in ECM remodeling. In contrast, MUO individuals showed lower expression of ECM components but elevated levels of ECM cross-linking and adhesion proteins, e.g., lysyl oxidase and thrombospondin. Our data suggests that subcutaneous fat is more prone to express proteins involved in ECM remodeling than omental adipose tissues. We conclude that a more dynamic ability to deposit and remodel ECM may be a key signature of healthy adipose tissue, and that subcutaneous fat may adapt more readily to changing metabolic conditions than omental fat.

Mechanisms for remodeling of connective tissue of the pelvic floor during pregnancy, childbirth and in the postpartum period

2021 ◽  
Vol 20 (2) ◽  
pp. 85-93
Author(s):  
S.N. Bayanova ◽  
◽  
L.S. Aleksandrov ◽  
A.I. Ishchenko ◽  
M.V. Pletnikov ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Postpartum Period ◽  
Molecular Mechanisms ◽  
Lysyl Oxidase ◽  
Elastic Fibers ◽  
Female Reproductive System ◽  
Triggering Mechanism ◽  
Polypeptide Chains ◽  
Connective Tissue Remodeling

The analysis of literature data on molecular mechanisms for remodeling of connective tissue of the female reproductive system during pregnancy, childbirth and in the postpartum period is presented. The search for publications and their analysis was conducted in PUBMED, Google Scholar, eLIBRARY.RU databases. Particular attention was given to the study of expression pattern of specific proteinases involved in the process of synthesis and combination of elastic fibers, assembly of the collagen polypeptide chains at different stages. The place of matrix metalloproteinases and their tissue inhibitors in proteolytic degradation of the extracellular matrix of connective tissue is described. Pregnancy, childbirth and postpartum period are the triggering mechanism for connective tissue remodeling, certain mechanisms of which remain unclear and require further investigation. Key words: collagen, lysyl oxidase, metalloproteinases, сonnective tissue, fibulin-5, extracellular matrix, elastic fibers

Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3979-3989 ◽  
Author(s):  
Marine Bignon ◽  
Cathy Pichol-Thievend ◽  
Julie Hardouin ◽  
Marilyne Malbouyres ◽  
Nicolas Bréchot ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Lysyl Oxidase ◽  
Collagen Iv ◽  
Ecm Remodeling ◽  
Capillary Formation ◽  
Fibrin Gels ◽  
Sprouting Angiogenesis ◽  
Type Iv ◽  
Endothelial Basement Membrane

Abstract Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.

scholarly journals Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Petra Büttner ◽  
Lukas Feistner ◽  
Philipp Lurz ◽  
Holger Thiele ◽  
Joshua D. Hutcheson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Valve Disease ◽  
Reverse Remodeling ◽  
Calcific Aortic Valve Disease ◽  
Ecm Remodeling ◽  
The Individual

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

scholarly journals Copper, an Abandoned Player Returning to the Wound Healing Battle

2021 ◽  
Author(s):  
Gadi Borkow ◽  
Eyal Melamed
Keyword(s):  
Wound Healing ◽  
Copper Oxide ◽  
Molecular Mechanisms ◽  
Copper Ions ◽  
Lysyl Oxidase ◽  
Wide Spectrum ◽  
Critical Role ◽  
Dermal Fibroblasts ◽  
Wound Dressings ◽  
Continuous Release

Copper has two key properties that endow it as an excellent active ingredient to be used in the “wound healing battle”. First, copper plays a key role in angiogenesis, dermal fibroblasts proliferation, upregulation of collagen and elastin fibers production by dermal fibroblasts, and it serves as a cofactor of Lysyl oxidase needed for efficient dermal extracellular matrix (ECM) protein cross-linking. Secondly, copper has potent wide-spectrum biocidal properties. Both gram-positive and gram-negative bacteria, including antibiotic resistant bacteria and hard to kill bacterial spores, fungi and viruses, when exposed to high copper concentrations, are killed. Copper has been used as a biocide for centuries by many different civilizations. Impregnation of copper oxide microparticles in wound dressings allows continuous release of copper ions. This results not only in the protection of the wounds and wound dressings from pathogens, but more importantly, enhances wound healing. The article discusses the molecular mechanisms of enhanced wound healing by the copper oxide impregnated dressings, which include in situ upregulation of pro-angiogenic factors and increased blood vessel formation. It also includes clinical cases showing clearance of infection, induction of granulation and epithelialization of necrotic wounds, reduction of post-operative swelling inflammation and reduction of scar formation, in wounds when they were treated with copper oxide impregnated dressings. We show the positive outcome at all wound healing stages of using the copper impregnated wound dressings, indicating the neglected critical role copper plays in wound healing.

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