E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene. [5]
E selectin has a cassette structure: an N-terminal, C-type lectin domain, an EGF (epidermal-growth-factor)-like domain, 6 Sushi domain (SCR repeat) units, a transmembrane domain (TM) and an intracellular cytoplasmic tail (cyto). The three-dimensional structure of the ligand-binding region of human E-selectin has been determined at 2.0 Å resolution in 1994. [6] The structure reveals limited contact between the two domains and a coordination of Ca2+ not predicted from other C-type lectins. Structure/function analysis indicates a defined region and specific amino-acid side chains that may be involved in ligand binding. The E-selectin bound to sialyl-LewisX (SLeX; NeuNAcα2,3Galβ1,4[Fucα1,3]GlcNAc) tetrasaccharide was solved in 2000. [7]
In humans, E-selectin is encoded by the SELE gene. Its C-type lectin domain, EGF-like, SCR repeats, and transmembrane domains are each encoded by separate exons, whereas the E-selectin cytosolic domain derives from two exons. The E-selectin locus flanks the L-selectin locus on chromosome 1. [8]
Different from P-selectin, which is stored in vesicles called Weibel-Palade bodies, E-selectin is not stored in the cell and has to be transcribed, translated, and transported to the cell surface. The production of E-selectin is stimulated by the expression of P-selectin which in turn, is stimulated by tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and lipopolysaccharide (LPS). [9] [10] It takes about two hours, after cytokine recognition, for E-selectin to be expressed on the endothelial cell's surface. Maximal expression of E-selectin occurs around 6–12 hours after cytokine stimulation, and levels returns to baseline within 24 hours. [10]
Shear forces are also found to affect E-selectin expression. A high laminar shear enhances acute endothelial cell response to interleukin-1β in naïve or shear-conditioned endothelial cells as may be found in the pathological setting of ischemia/reperfusion injury while conferring rapid E-selectin down regulation to protect against chronic inflammation. [11]
Phytoestrogens, plant compounds with estrogen-like biological activity, such as genistein, formononetin, biochanin A and daidzein, as well as a mixture of these phytoestrogens were found able to reduce E-selectin as well as VCAM-1 and ICAM-1 on cell surface and in culture supernatant. [12]
E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. E-selectin ligands are expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, and natural killer cells. Each of these cell types is found in acute and chronic inflammatory sites in association with expression of E-selectin, thus implicating E-selectin in the recruitment of these cells to such inflammatory sites.
These carbohydrates include members of the Lewis X and Lewis A families found on monocytes, granulocytes, and T-lymphocytes. [13]
The glycoprotein ESL-1, present on neutrophils and myeloid cells, was the first counter-receptor for E-selectin to be described. It is a variant of the tyrosine kinase FGF glycoreceptor, raising the possibility that its binding to E-selectin is involved in initiating signaling in the bound cells.
P-selectin glycoprotein ligand-1 (PSGL-1) derived from human neutrophils is also a high-efficiency ligand for endothelium-expressed E-selectin under flow. [14] It mediates the rolling of leukocytes on the activated endothelium surrounding an inflamed tissue.
Both ESL-1 and PSGL-1 should bear sialyl Lewis a/x in order to bind E/P-selectins. [15]
E-selectin is found to mediate the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands on the tumor cells. E-selectin ligands also play a role in cancer metastasis. The role of these two E-selectin ligands in metastasis in vivo is poorly defined and remains to be firmly demonstrated. PSGL-1 was detected on the surfaces of bone-metastatic prostate tumor cells, suggesting that it may have a functional role in the bone tropism of prostate tumor cells. [16]
In cancer cells, CD44, death receptor-3 (DR3), LAMP1, and LAMP2 were identified as E-selectin ligands present on colon cancer cells, [17] and CD44v, Mac2-BP, and gangliosides were identified as E-selectin ligands present on breast cancer cells. [18] [19] [20]
On human neutrophils the glycosphingolipid NeuAcα2-3Galβ1-4GlcNAcβ1-3[Galβ1-4(Fucα1-3)GlcNAcβ1-3]2[Galβ1-4GlcNAcβ1-3]2Galβ1-4GlcβCer (and closely related structures) are functional E-selectin receptors. [21]
During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. The local release of cytokines IL-1 and TNF-α by macrophages in the inflamed tissue induces the over-expression of E-selectin on endothelial cells of nearby blood vessels. [22] Leukocytes in the blood expressing the correct ligand will bind with low affinity to E-selectin, also under the shear stress of blood flow, causing the leukocytes to "roll" along the internal surface of the blood vessel as temporary interactions are made and broken.
As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue. [13]
P-selectin has a similar function, but is expressed on the endothelial cell surface within minutes as it is stored within the cell rather than produced on demand. [13]
E-selectin was first discovered as an transmembrane receptor induced in endothelial cells upon inflammatory stimulation which mediated adhesion of monocytic or HL60 leukemic cells. [23] [24] This led to the hypothesis that cancer cells secreted inflammatory cytokines such as IL-1β or TNFα to induce E-selectin at distant metastatic sites. This induction would enable circulating tumor cells to arrest at stimulated sites, roll along activated endothelium, extravasate, and form metastases. [25] Studies since have showed that E-selectin binding to colon cancer cells correlates with increasing metastatic potential, [26] and that cancer cells of multiple tumor types bind E-selectin using glycoprotein or glycolipid ligands normally expressed on immune cells. [27] [28] Studies have further described a mechanistic cascade wherein cancer cells first bind E-selectin at shear flow rates: E-selectin binding results in a velcro-like interaction allowing the cancer cells to engage higher affinity integrin binding that eventually results in a tight binding between tumor cells and the activated endothelium. [29] [30]
While numerous pieces of in vitro and clinical evidence continue to support this hypothesis of E-selectin-mediated cancer metastasis, in vivo studies of cancer metastasis have shown that E-selectin knockout only minimally affects leukemic cell adhesion to bone immediately following injection. [31] while experimental lung metastasis is not affected by the genetic deletion of E-selectin. [32] [33] Furthermore, studies have also shown that primary tumor growth is increased in E-selectin knockout mice. [34] [35] This paradox was more recently solved by a trio of studies showing that E-selectin is only constitutively expressed in the bone marrow endothelium [36] where it is thought to perform functions vital to hematopoiesis. [37] that are hijacked specifically by cells metastasizing to bone and not other sites. [38] This data supports ongoing clinical efforts to inhibit breast cancer bone metastasis with E-selectin-blocking agents. [39] The complexity of E-selectin ligand biology may also play a role in these discrepant in vitro and in vivo results. At least 15 different glycoprotein and glycolipid substrates for E-selectin have been described on various cancer cells, while only n-glycan Glg1 (Esl1) was shown to mediate bone metastasis. [40] Other ligands or combinations thereof may result in distinct mechanisms during cancer metastasis.
Beyond a direct interaction with tumor cells, E-selectin induction in response to cytokines locally secreted by cancer cells enables specific tumor targeting of sLeX-conjugated nanoparticles or thioaptamers containing anti-tumor payloads. [41] In addition, E-selectin may also function to recruit monocytes to primary tumors or lung metastases to promote an inflammatory pro-tumor microenvironment. [42] Blocking these interactions or enabling trafficking of CAR-T cells to E-selectin-positive sites may hold promise for future therapeutic development.
In cases of elevated blood glucose levels, such as in sepsis, E-selectin expression is higher than normal, resulting in greater microvascular permeability. The greater permeability leads to edema (swelling) of the skeletal endothelium (blood vessel linings), resulting in skeletal muscle ischemia (restricted blood supply) and eventually necrosis (cell death). This underlying pathology is the cause of the symptomatic disease critical illness polyneuromyopathy (CIPNM). [43] Traditional Chinese herbal medicines, like berberine downregulate E-selectin. [44]
Study shows the adherence of Porphyromonas gingivalis to human umbilical vein endothelial cells increases with the induction of E-selectin expression by TNF-α. An antibody to E-selectin and sialyl LewisX suppressed P. gingivalis adherence to stimulated HUVECs. P. gingivalis mutants lacking OmpA-like proteins Pgm6/7 had reduced adherence to stimulated HUVECs, but fimbriae-deficient mutants were not affected. E-selecin-mediated P. gingivalis adherence activated endothelial exocytosis. These results suggest that the interaction between host E-selectin and pathogen Pgm6/7 mediates P. gingivalis adherence to endothelial cells and may trigger vascular inflammation. [45]
The immunohistochemical expressions of E-selectin and PECAM-1 were significantly increased at intima in vulnerable plaques of acute coronary syndrome (ACS) group, especially in neovascular endothelial cells, and positively correlated with inflammatory cell density, suggesting that PECAM-1 and E-selectin might play an important role in inflammatory reaction and development of vulnerable plaque. E-selectin Ser128Arg polymorphism is associated with ACS, and it might be a risk factor for ACS. [46]
Smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction. In endothelial cells, various cell-adhesion molecules including E-selectin, are shown to be upregulated upon exposure to nicotine, the addictive component of tobacco smoke. Nicotine-stimulated adhesion of monocytes to endothelial cells is dependent on the activation of α7-nAChRs, β-Arr1 and cSrc regulated increase in E2F1-mediated transcription of E-selectin gene. Therefore, agents such as RRD-251 that can target activity of E2F1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis. [47]
It's also found that E-selectin expression increased in human ruptured cerebral aneurysm tissues. E-selectin might be an important factor involved in the process of cerebral aneurysm formation and rupture, by promoting inflammation and weakening cerebral artery walls. [48]
E-selectin is also an emerging biomarker for the metastatic potential of some cancers including colorectal cancer and recurrences. [49]
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.
Selectin P ligand, also known as SELPLG or CD162, is a human gene.
The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.
Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.
The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.
ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.
L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.
Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.
Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.
CD146 also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.
Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.
Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene. CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT7 gene.
Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.
Endothelial cell anergy is a condition during the process of angiogenesis, where endothelial cells, the cells that line the inside of blood vessels, can no longer respond to inflammatory cytokines. These cytokines are necessary to induce the expression of cell adhesion molecules to allow leukocyte infiltration from the blood into the tissue at places of inflammation, such as a tumor. This condition, which protects the tumor from the immune system, is the result of exposure to angiogenic growth factors.
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