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Advanced Science (Weinheim,... Jun 2023Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the...
Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism.
Topics: Transendothelial and Transepithelial Migration; Endothelial Cells; Endothelium; Actins; Mechanical Phenomena; Neoplasms
PubMed: 37051804
DOI: 10.1002/advs.202206554 -
Cellular and Molecular Life Sciences :... Sep 2012Leukocyte trafficking from the bloodstream to inflamed tissues across the endothelial barrier is an essential response in innate immunity. Leukocyte adhesion,... (Review)
Review
Leukocyte trafficking from the bloodstream to inflamed tissues across the endothelial barrier is an essential response in innate immunity. Leukocyte adhesion, locomotion, and diapedesis induce signaling in endothelial cells and this is accompanied by a profound reorganization of the endothelial cell surfaces that is only starting to be unveiled. Here we review the current knowledge on the leukocyte-mediated alterations of endothelial membrane dynamics and their role in promoting leukocyte extravasation. The formation of protein- and lipid-mediated cell adhesion nanodomains at the endothelial apical surface, the extension of micrometric apical membrane docking structures, which are derived from microvilli and embrace adhered leukocytes, as well as the vesicle-trafficking pathways that are required for efficient leukocyte diapedesis, are discussed. The coordination between these different endothelial membrane-remodeling events probably provides the road map for transmigrating leukocytes to find exit points in the vessel wall, in a context of severe mechanical and inflammatory stress. A better understanding of how vascular endothelial cells respond to immune cell adhesion should enable new therapeutic strategies to be developed that can abrogate uncontrolled leukocyte extravasation in inflammatory diseases.
Topics: Actins; Animals; Antigens, CD; Caveolae; Cell Adhesion; Cell Adhesion Molecules; Cell Membrane; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Leukocytes; Membrane Microdomains; Microvilli; Tetraspanins; Transendothelial and Transepithelial Migration; Vimentin
PubMed: 22573182
DOI: 10.1007/s00018-012-0987-4 -
Journal of Cell Science Apr 2021During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm... (Review)
Review
During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm of this process comprises several well-established steps, including rolling, adhesion, crawling, diapedesis and sub-endothelial crawling. Nowadays, the role of the endothelium in transmigration is increasingly appreciated. It has been established that leukocyte exit sites on the endothelium and in the pericyte layer are in fact not random but instead may be specifically recognized by migrating leukocytes. Here, we review the concept of transmigration hotspots, specific sites in the endothelial and pericyte layer where most transmigration events take place. Chemokine cues, adhesion molecules and membrane protrusions as well as physical factors, such as endothelial junction stability, substrate stiffness, the presence of pericytes and basement membrane composition, may all contribute to local hotspot formation to facilitate leukocytes exiting the vasculature. In this Review, we discuss the biological relevance of such hotspots and put forward multiple mechanisms and factors that determine a functional TEM hotspot.
Topics: Cell Adhesion Molecules; Endothelium, Vascular; Leukocytes; Neutrophils; Pericytes; Transendothelial and Transepithelial Migration
PubMed: 33795378
DOI: 10.1242/jcs.255653 -
Brain : a Journal of Neurology Nov 2019Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell...
Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, we identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. These cells used their high levels of VLA-4 to arrest on scattered VCAM1, their open-conformation LFA-1 to crawl preferentially against the flow in search for sites permissive for extravasation, and their stored granzyme K (GZMK) to induce local ICAM1 aggregation and perform trans-, rather than paracellular diapedesis through unstimulated primary brain microvascular endothelial cells. This study included peripheral blood mononuclear cell samples from 175 healthy donors, 29 patients infected with HIV, with neurological symptoms in terms of cognitive impairment, 73 patients with relapsing-remitting multiple sclerosis in remission, either 1-4 weeks before (n = 29), or 18-60 months after the initiation of natalizumab therapy (n = 44), as well as white matter brain tissue of three patients suffering from epilepsy. We here provide ex vivo evidence that CCR5highGZMK+CD4+ effector memory T cells are involved in CNS immune surveillance during homeostasis, but could also play a role in CNS pathology. Among CD4+ T cells, this subset was found to dominate the CNS of patients without neurological inflammation ex vivo. The reduction in peripheral blood of HIV-positive patients with neurological symptoms correlated to their CD4 count as a measure of disease progression. Their peripheral enrichment in multiple sclerosis patients and specific peripheral entrapment through the CNS infiltration inhibiting drug natalizumab additionally suggests a contribution to CNS autoimmune pathology. Our transcriptome analysis revealed a migratory phenotype sharing many features with tissue-resident memory and Th17.1 cells, most notably the transcription factor eomesodermin. Knowledge on this cell subset should enable future studies to find ways to strengthen the host defence against CNS-resident pathogens and brain tumours or to prevent CNS autoimmunity.
Topics: AIDS Dementia Complex; Adult; CD4-Positive T-Lymphocytes; Endothelial Cells; Epilepsy; Granzymes; Humans; Immunologic Surveillance; Intercellular Adhesion Molecule-1; Multiple Sclerosis, Relapsing-Remitting; Receptors, CCR5; Transendothelial and Transepithelial Migration; Vascular Cell Adhesion Molecule-1
PubMed: 31563951
DOI: 10.1093/brain/awz301 -
Veterinary Pathology Jan 2013There is no "response" in either the innate or adaptive immune response unless leukocytes cross blood vessels. They do this through the process of diapedesis, in which... (Review)
Review
There is no "response" in either the innate or adaptive immune response unless leukocytes cross blood vessels. They do this through the process of diapedesis, in which the leukocyte moves in ameboid fashion through tightly apposed endothelial borders (paracellular transmigration) and in some cases through the endothelial cell itself (transcellular migration). This review summarizes the steps leading up to diapedesis, then focuses on the molecules and mechanisms responsible for transendothelial migration. Surprisingly, many of the same molecules and mechanisms that regulate paracellular migration also control transcellular migration, including a major role for membrane from the recently described lateral border recycling compartment. A hypothesis that integrates the various known mechanisms of transmigration is proposed.
Topics: Animals; Cell Adhesion Molecules; Endothelial Cells; Humans; Inflammation; Leukocytes; Mice; Models, Biological; Transendothelial and Transepithelial Migration
PubMed: 23345459
DOI: 10.1177/0300985812469883 -
Journal of Cell Science Feb 2021The migration of circulating neutrophils towards damaged or infected tissue is absolutely critical to the inflammatory response. L-selectin is a cell adhesion molecule...
The migration of circulating neutrophils towards damaged or infected tissue is absolutely critical to the inflammatory response. L-selectin is a cell adhesion molecule abundantly expressed on circulating neutrophils. For over two decades, neutrophil L-selectin has been assigned the exclusive role of supporting tethering and rolling - the initial stages of the multi-step adhesion cascade. Here, we provide direct evidence for L-selectin contributing to neutrophil transendothelial migration (TEM). We show that L-selectin co-clusters with PECAM-1 - a well-characterised cell adhesion molecule involved in regulating neutrophil TEM. This co-clustering behaviour occurs specifically during TEM, which serves to augment ectodomain shedding of L-selectin and expedite the time taken for TEM (TTT) to complete. Blocking PECAM-1 signalling (through mutation of its cytoplasmic tail), PECAM-1-dependent adhesion or L-selectin shedding, leads to a significant delay in the TTT. Finally, we show that co-clustering of L-selectin with PECAM-1 occurs specifically across TNF- but not IL-1β-activated endothelial monolayers - implying unique adhesion interactomes forming in a cytokine-specific manner. To our knowledge, this is the first report to implicate a non-canonical role for L-selectin in regulating neutrophil TEM.
Topics: Cell Adhesion; Cell Movement; Endothelium, Vascular; Humans; L-Selectin; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 33408247
DOI: 10.1242/jcs.250340 -
Cellular Immunology 2011To invade a tissue, leukocytes have to overcome the endothelial barrier. Prior to trans-endothelial migration, leukocytes move laterally on the endothelial...
To invade a tissue, leukocytes have to overcome the endothelial barrier. Prior to trans-endothelial migration, leukocytes move laterally on the endothelial surface-searching for an emigration site. It is still unclear, how the actual diapedesis step is initiated and whether the endothelium has a decisive role. Here, video-microscopy was employed to investigate, whether lateral migration of leukocytes is correlated to their diapedesis rate. To address the contribution of each cell type, selective stimulation of either leukocytes or endothelial cells with TNFα was performed. Stimulation of endothelial cells alone was sufficient for maximal effects, thereby underlining their decisive role for leukocyte diapedesis. Concomitant to the TNFα-enhanced diapedesis rate, leukocyte adhesion was intensified and, unexpectedly, the lateral leukocyte migration was accelerated.
Topics: Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Humans; Kinetics; Leukocytes; Microscopy, Video; Neutrophils; Time Factors; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha
PubMed: 21764046
DOI: 10.1016/j.cellimm.2011.06.022 -
Trends in Immunology May 2016Neutrophil migration to injured and pathogen-infected tissues is a fundamental component of innate immunity. An array of cellular and molecular events mediate this... (Review)
Review
Neutrophil migration to injured and pathogen-infected tissues is a fundamental component of innate immunity. An array of cellular and molecular events mediate this response to collectively guide neutrophils out of the vasculature and towards the core of the ensuing inflammatory reaction where they exert effector functions. Advances in imaging modalities have revealed that neutrophils can also exhibit motility away from sites of inflammation and injury, although it is unclear under what circumstances this reverse migration is a physiological protective response, and when it has pathophysiological relevance. Here we review different types of neutrophil reverse migration and discuss the current understanding of the associated mechanisms. In this context we propose clarifications to the existing terminology used to describe the many facets of neutrophil reverse migration.
Topics: Animals; Cell Movement; Endothelium, Vascular; Humans; Immunity, Innate; Inflammation; Neutrophil Activation; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 27055913
DOI: 10.1016/j.it.2016.03.006 -
European Journal of Immunology Apr 2015The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune...
The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM-1, promoted rapid initiation of transcellular diapedesis of CD4(+) T cells across the BBB, while intermediate levels of endothelial ICAM-1 favored paracellular CD4(+) T-cell diapedesis. Importantly, the route of T-cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4(+) TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM-1 and ICAM-2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM-1(null) //ICAM-2(-/-) C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM-1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T-cell diapedesis across the BBB.
Topics: Animals; Antigens, CD; Blood-Brain Barrier; CD4-Positive T-Lymphocytes; Cell Adhesion; Cell Adhesion Molecules; Encephalomyelitis, Autoimmune, Experimental; Endothelial Cells; Female; Immunologic Memory; Inflammation; Intercellular Adhesion Molecule-1; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Transendothelial and Transepithelial Migration
PubMed: 25545837
DOI: 10.1002/eji.201445125 -
Immunological Reviews Sep 2016Transendothelial migration (TEM) of polymorphonuclear leukocytes (PMN) involves a carefully orchestrated dialog of adhesion and signaling events between leukocyte and... (Review)
Review
Transendothelial migration (TEM) of polymorphonuclear leukocytes (PMN) involves a carefully orchestrated dialog of adhesion and signaling events between leukocyte and endothelial cell. This article focuses on the contribution of endothelial cells to transmigration. The initiation of TEM itself generally requires interaction of PECAM on the leukocyte with PECAM at the endothelial cell border. This is responsible for the transient elevation of cytosolic-free calcium ions in endothelium that is required for TEM and for recruitment of membrane from the lateral border recycling compartment (LBRC). TEM requires LBRC to move to the site at which TEM will take place and for VE-cadherin to move away. Targeting of the LBRC to this site likely precedes movement of VE-cadherin and may play a role in clearing VE-cadherin from the site of TEM. The process of TEM can be dissected into steps mediated by distinct pairs of PMN/endothelial interacting molecules. CD99 regulates a step at or close to the end of TEM. CD99 signals through soluble adenylyl cyclase to activate PKA to trigger ongoing targeted recycling of the LBRC. Paracellular transmigration predominates (≥90% of events) in the cremaster muscle circulation, but transcellular migration may be more important at sites such as the blood-brain barrier. Both processes involve many of the same molecules and recruitment of the LBRC.
Topics: Abdominal Muscles; Animals; Blood-Brain Barrier; Calcium Signaling; Endothelial Cells; Humans; Neutrophils; Platelet Endothelial Cell Adhesion Molecule-1; Protein Transport; Transendothelial and Transepithelial Migration
PubMed: 27558328
DOI: 10.1111/imr.12443