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International Journal of Molecular... Jan 2013The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to... (Review)
Review
The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB). The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation.
Topics: Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Melanoma; Models, Biological; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 23344048
DOI: 10.3390/ijms14011383 -
International Journal of Molecular... May 2022Endothelial dysfunction during diabetes has been previously reported to be at least in part attributed to increased oxidized low‑density lipoprotein (oxLDL) levels...
Endothelial dysfunction during diabetes has been previously reported to be at least in part attributed to increased oxidized low‑density lipoprotein (oxLDL) levels mediated by high glucose (HG) levels. Endothelial inflammation increases the adhesiveness of monocytes to the endothelium in addition to increasing vascular permeability, promoting diabetic atherogenesis. In a previous study, it was reported that oxLDL treatment induced nucleotide‑binding domain and leucine‑rich repeat containing family, pyrin domain‑containing 3 inflammasome activation in endothelial cells (ECs) under HG conditions, in a manner that could be effectively reversed by rosmarinic acid. However, it remains unclear whether oxLDL‑mediated inflammasome activation can regulate the interaction between monocytes and ECs. The effects of oxLDL‑mediated inflammasome activation on endothelial permeability under HG conditions, in addition to the effects of rosmarinic acid on these oxLDL‑mediated processes, also remain poorly understood. Therefore, the present study aimed to elucidate the mechanisms involved in oxLDL‑induced endothelial permeability and monocyte diapedesis under HG conditions, in addition to the potential effects of rosmarinic acid. ECs were treated with oxLDL under HG conditions in the presence or absence of ROS scavengers mitoTEMPO and NAC, p38 inhibitor SB203580, FOXO1 inhibitor AS1842856 or transfected with the TXNIP siRNA, before protein expression levels of intercellular adhesion molecule 1 (ICAM‑1), vascular cell adhesion molecule‑1 (VCAM‑1), phosphorylated vascular endothelial‑cadherin (VE‑cadhedrin), VE‑cadherin and zonula occludens‑1 (ZO‑1) were measured by western blotting. In addition, adhesion assay and Transwell assays were performed. oxLDL was found to significantly increase the expression of ICAM‑1 and VCAM‑1 in ECs under HG conditions whilst also enhancing the adhesion of monocytes to ECs. This was found to be dependent on the reactive oxygen species (ROS)/p38 MAPK/forkhead box O1 (FOXO1)/thioredoxin interacting protein (TXNIP) signaling pathway. In addition, oxLDL‑stimulated ECs under HG conditions exhibited increased phosphorylated VE‑cadherin protein levels and decreased ZO‑1 protein expression levels compared with those in untreated ECs, suggesting increased endothelial permeability. Furthermore, monocyte transmigration through the endothelial monolayer was significantly increased by oxLDL treatment under HG conditions. These oxLDL‑mediated effects under HG conditions were also demonstrated to be dependent on this ROS/p38 MAPK/FOXO1/TXNIP signaling pathway. Subsequently, rosmarinic acid treatment significantly reversed oxLDL‑induced overexpression of adhesion molecules and monocyte‑EC adhesion, oxLDL‑induced endothelial junction hyperpermeability and monocyte transmigration through the endothelial monolayer under HG conditions, in a dose‑dependent manner. These results suggest that rosmarinic acid can exert a protective effect against oxLDL‑mediated endothelial dysfunction under HG conditions by reducing the interaction between monocytes and ECs in addition to preventing monocyte diapedesis.
Topics: Cell Adhesion; Cinnamates; Depsides; Endothelial Cells; Glucose; Lipoproteins, LDL; Monocytes; Transendothelial and Transepithelial Migration; Rosmarinic Acid
PubMed: 35315501
DOI: 10.3892/ijmm.2022.5125 -
Nucleus (Austin, Tex.) Sep 2016Immune cells react to a wide range of environments, both chemical and physical. While the former has been extensively studied, there is growing evidence that physical... (Review)
Review
Immune cells react to a wide range of environments, both chemical and physical. While the former has been extensively studied, there is growing evidence that physical and in particular mechanical forces also affect immune cell behavior and development. In order to elicit a response that affects immune cell behavior or development, environmental signals must often reach the nucleus. Chemical and mechanical signals can initiate signal transduction pathways, but mechanical forces may also have a more direct route to the nucleus, altering nuclear shape via mechanotransduction. The three-dimensional organization of DNA allows for the possibility that altering nuclear shape directly remodels chromatin, redistributing critical regulatory elements and proteins, and resulting in wide-scale gene expression changes. As such, integrating mechanotransduction and genome architecture into the immunology toolkit will improve our understanding of immune development and disease.
Topics: Animals; Cell Differentiation; Cell Shape; Genome; Humans; Immunity; Mechanotransduction, Cellular; Transendothelial and Transepithelial Migration
PubMed: 27673560
DOI: 10.1080/19491034.2016.1238998 -
Mutation Research 2011Metastasis is the leading cause of cancer mortality. The metastatic cascade represents a multi-step process which includes local tumor cell invasion, entry into the... (Review)
Review
Metastasis is the leading cause of cancer mortality. The metastatic cascade represents a multi-step process which includes local tumor cell invasion, entry into the vasculature followed by the exit of carcinoma cells from the circulation and colonization at the distal sites. At the earliest stage of successful cancer cell dissemination, the primary cancer adapts the secondary site of tumor colonization involving the tumor-stroma crosstalk. The migration and plasticity of cancer cells as well as the surrounding environment such as stromal and endothelial cells are mandatory. Consequently, the mechanisms of cell movement are of utmost relevance for targeted intervention of which three different types have been reported. Tumor cells can migrate either collectively, in a mesenchymal or in an amoeboid type of movement and intravasate the blood or lymph vasculature. Intravasation by the interaction of tumor cells with the vascular endothelium is mechanistically poorly understood. Changes in the epithelial plasticity enable carcinoma cells to switch between these types of motility. The types of migration may change depending on the intervention thereby increasing the velocity and aggressiveness of invading cancer cells. Interference with collective or mesenchymal cell invasion by targeting integrin expression or metalloproteinase activity, respectively, resulted in an amoeboid cell phenotype as the ultimate exit strategy of cancer cells. There are little mechanistic details reported in vivo showing that the amoeboid behavior can be either reversed or efficiently inhibited. Future concepts of metastasis intervention must simultaneously address the collective, mesenchymal and amoeboid mechanisms of cell invasion in order to advance in anti-metastatic strategies as these different types of movement can coexist and cooperate. Beyond the targeting of cell movements, the adhesion of cancer cells to the stroma in heterotypic circulating tumor cell emboli is of paramount relevance for anti-metastatic therapy.
Topics: Cell Movement; Humans; Mesoderm; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Transendothelial and Transepithelial Migration; Tumor Microenvironment
PubMed: 21605699
DOI: 10.1016/j.mrrev.2011.05.002 -
International Journal of Molecular... Jun 2022In inflammatory diseases, polymorphonuclear neutrophils (PMNs) are known to produce elevated levels of pro-inflammatory cytokines and proteases. To limit ensuing...
In inflammatory diseases, polymorphonuclear neutrophils (PMNs) are known to produce elevated levels of pro-inflammatory cytokines and proteases. To limit ensuing exacerbated cell responses and tissue damage, novel therapeutic agents are sought. 4aa and 4ba, two pyridazinone-scaffold-based phosphodiesterase-IV inhibitors are compared in vitro to zardaverine for their ability to: (1) modulate production of pro-inflammatory mediators, reactive oxygen species (ROS), and phagocytosis; (2) modulate degranulation by PMNs after transepithelial lung migration. Compound 4ba and zardaverine were tested in vivo for their ability to limit tissue recruitment of PMNs in a murine air pouch model. In vitro treatment of lipopolysaccharide-stimulated PMNs with compounds 4aa and 4ba inhibited the release of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9. PMNs phagocytic ability, but not ROS production, was reduced following treatment. Using a lung inflammation model, we proved that PMNs transmigration led to reduced expression of the CD16 phagocytic receptor, which was significantly blunted after treatment with compound 4ba or zardaverine. Using the murine air pouch model, LPS-induced PMNs recruitment was significantly decreased upon addition of compound 4ba or zardaverine. Our data suggest that new pyridazinone derivatives have therapeutic potential in inflammatory diseases by limiting tissue recruitment and activation of PMNs.
Topics: Animals; Lipopolysaccharides; Mice; Neutrophils; Phagocytosis; Reactive Oxygen Species; Transendothelial and Transepithelial Migration
PubMed: 35806233
DOI: 10.3390/ijms23137226 -
Journal of Biomechanics May 2021During cancer metastasis, tumor cells undergo significant deformation in order to traverse through endothelial cell junctions in the walls of blood vessels. As cells...
During cancer metastasis, tumor cells undergo significant deformation in order to traverse through endothelial cell junctions in the walls of blood vessels. As cells pass through narrow gaps, smaller than the nuclear diameter, the spatial configuration of chromatin must change along with the distribution of nuclear enzymes. Nuclear stiffness is an important determinant of the ability of cells to undergo transendothelial migration, yet no studies have been conducted to assess whether tumor cell cytoskeletal or nuclear stiffness changes during this critical process in order to facilitate passage. To address this question, we employed two non-contact methods, Brillouin confocal microscopy (BCM) and confocal reflectance quantitative phase microscopy (QPM), to track the changes in mechanical properties of live, transmigrating tumor cells in an in vitro collagen gel platform. Using these two imaging modalities to study transmigrating MDA-MB-231, A549, and A375 cells, we found that both the cells and their nuclei soften upon extravasation and that the nuclear membranes remain soft for at least 24 h. These new data suggest that tumor cells adjust their mechanical properties in order to facilitate extravasation.
Topics: Cell Line, Tumor; Cell Movement; Cell Nucleus; Collagen; Humans; Microscopy, Confocal; Neoplasms; Transendothelial and Transepithelial Migration
PubMed: 33882444
DOI: 10.1016/j.jbiomech.2021.110400 -
European Journal of Immunology Oct 2011Macrophage tissue infiltration is a hallmark of several pathological situations including cancer, neurodegenerative disorders and chronic inflammation. Hence,... (Review)
Review
Macrophage tissue infiltration is a hallmark of several pathological situations including cancer, neurodegenerative disorders and chronic inflammation. Hence, deciphering the mechanisms of macrophage migration across a variety of tissues holds great potential for novel anti-inflammatory therapies. Leukocytes have long been thought to migrate through tissues by using the amoeboid (protease-independent) migration mode; however, recent evidence indicates that macrophages can use either the amoeboid or the mesenchymal (protease-dependent) migration mode depending on the environmental constraints. Proteolytic activity is required for several key processes including cell migration. Paradoxically, the role of proteases in macrophage migration has been poorly studied. Here, by focusing on the best characterized extracellular protease families - MMPs, cathepsins and urokinase-type plasminogen activator - we give an overview of their probable involvement in macrophage migration. These proteases appear to play a role in all of the situations encountered by migrating macrophages, i.e. diapedesis, 2D and 3D migration. Migration of macrophages across tissues seems to proceed through an integrative analysis of numerous environmental clues allowing the cells to adapt their migration mode (amoeboid/mesenchymal) and secrete dedicated proteases to ensure efficient tissue infiltration, as discussed in this review. The role of proteases in macrophage migration is an emerging field of research, which deserves further work to allow a more precise understanding.
Topics: Animals; Anti-Inflammatory Agents; Cathepsins; Cell Movement; Extracellular Matrix; Humans; Leukocytes; Macrophages; Matrix Metalloproteinases; Transendothelial and Transepithelial Migration; Urokinase-Type Plasminogen Activator
PubMed: 21953638
DOI: 10.1002/eji.201141538 -
Current Opinion in Hematology Jan 2016Neutrophils have traditionally been viewed in the context of acute infection and inflammation forming the first line of defense against invading pathogens. Neutrophil... (Review)
Review
PURPOSE OF REVIEW
Neutrophils have traditionally been viewed in the context of acute infection and inflammation forming the first line of defense against invading pathogens. Neutrophil trafficking to the site of inflammation requires adhesion and transmigration through blood vessels, which is orchestrated by adhesion molecules, such as β2 and β1-integrins, chemokines, and cytokines. The review focuses on recent advances in understanding the regulators of neutrophil recruitment during inflammation in both acute and chronic settings.
RECENT FINDINGS
Recent findings suggest that besides the established pathways of selectin or chemokine-mediated integrin activation, signaling by distinct Toll-like receptors (TLRs) (especially TLR2, TLR4, and TLR5) can activate integrin-dependent neutrophil adhesion. Moreover, the integrin α3β1 has been vitally implicated as a new player in neutrophil recruitment and TLR-mediated responses in septic inflammation. Furthermore, several endogenous inhibitory mechanisms of leukocyte recruitment have been identified, including the secreted molecules Del-1, PTX3, and GDF-15, which block distinct steps of the leukocyte adhesion cascade, as well as novel regulatory signaling pathways, involving the protein kinase AKT1 and IFN-λ2/IL-28A.
SUMMARY
The leukocyte adhesion cascade is a tightly regulated process, subjected to both positive and negative regulators. Dysregulation of this process and hence neutrophil recruitment can lead to the development of inflammatory and autoimmune diseases.
Topics: Animals; Cell Adhesion; Chemokines; Homeostasis; Humans; Integrin alpha3beta1; Neutrophil Infiltration; Neutrophils; Protein Binding; Selectins; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 26554893
DOI: 10.1097/MOH.0000000000000198 -
EMBO Reports Apr 2023Pseudomonas aeruginosa is a Gram-negative bacterium causing morbidity and mortality in immuno-compromised humans. It produces a lectin, LecB, that is considered a major...
Pseudomonas aeruginosa is a Gram-negative bacterium causing morbidity and mortality in immuno-compromised humans. It produces a lectin, LecB, that is considered a major virulence factor, however, its impact on the immune system remains incompletely understood. Here we show that LecB binds to endothelial cells in human skin and mice and disrupts the transendothelial passage of leukocytes in vitro. It impairs the migration of dendritic cells into the paracortex of lymph nodes leading to a reduced antigen-specific T cell response. Under the effect of the lectin, endothelial cells undergo profound cellular changes resulting in endocytosis and degradation of the junctional protein VE-cadherin, formation of an actin rim, and arrested cell motility. This likely negatively impacts the capacity of endothelial cells to respond to extracellular stimuli and to generate the intercellular gaps for allowing leukocyte diapedesis. A LecB inhibitor can restore dendritic cell migration and T cell activation, underlining the importance of LecB antagonism to reactivate the immune response against P. aeruginosa infection.
Topics: Humans; Animals; Mice; Pseudomonas aeruginosa; Transendothelial and Transepithelial Migration; Endothelial Cells; Lectins; Immunity
PubMed: 36856136
DOI: 10.15252/embr.202255971 -
Mediators of Inflammation 2015Leukocyte extravasation is one of the essential and first steps during the initiation of inflammation. Therefore, a better understanding of the key molecules that... (Review)
Review
Leukocyte extravasation is one of the essential and first steps during the initiation of inflammation. Therefore, a better understanding of the key molecules that regulate this process may help to develop novel therapeutics for treatment of inflammation-based diseases such as atherosclerosis or rheumatoid arthritis. The endothelial adhesion molecules ICAM-1 and VCAM-1 are known as the central mediators of leukocyte adhesion to and transmigration across the endothelium. Engagement of these molecules by their leukocyte integrin receptors initiates the activation of several signaling pathways within both leukocytes and endothelium. Several of such events have been described to occur during transendothelial migration of all leukocyte subsets, whereas other mechanisms are known only for a single leukocyte subset. Here, we summarize current knowledge on regulatory mechanisms of leukocyte extravasation from a leukocyte and endothelial point of view, respectively. Specifically, we will focus on highlighting common and unique mechanisms that specific leukocyte subsets exploit to succeed in crossing endothelial monolayers.
Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Mice; Models, Biological; Transendothelial and Transepithelial Migration; Vascular Cell Adhesion Molecule-1
PubMed: 26568666
DOI: 10.1155/2015/946509