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Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers.

ABSTRACT: The tetrasaccharide structures Sia?2,3Gal?1,3(Fuc?1,4)GlcNAc and Sia?2,3Gal?1,4(Fuc?1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolling of cancer cells ectopically expressing the selectin ligands on endothelial cells is potentially a crucial step favoring the metastatic process. In this review, we focus on the biosynthetic steps giving rise to selectin ligand expression in cell lines and native tissues of gastrointestinal origin, trying to understand whether and how they are deregulated in cancer. We also discuss the use of such molecules in the diagnosis of gastrointestinal cancers, particularly in light of recent data questioning the ability of colon cancers to express sLea and the possible use of circulating sLex in the early detection of pancreatic cancer. Finally, we reviewed the data dealing with the mechanisms that link selectin ligand expression in gastrointestinal cells to cancer malignancy. This promising research field seems to require additional data on native patient tissues to reach more definitive conclusions.

SUBMITTER: Trinchera M

PROVIDER: S-EPMC5372009 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers.

Trinchera Marco M Aronica Adele A Dall'Olio Fabio F

Biology 20170223 1

The tetrasaccharide structures Siaα2,3Galβ1,3(Fucα1,4)GlcNAc and Siaα2,3Galβ1,4(Fucα1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolli ...[more]

PMID: 28241499

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Project description:BackgroundDuring inflammation, leukocytes are captured by the selectin family of adhesion receptors lining blood vessels to facilitate exit from the bloodstream. E-selectin is upregulated on stimulated endothelial cells and binds to several ligands on the surface of leukocytes. Selectin:ligand interactions are mediated in part by the interaction between the lectin domain and Sialyl-Lewis x (sLe(x)), a tetrasaccharide common to selectin ligands. There is a high degree of homology between selectins of various species: about 72 and 60 % in the lectin and EGF domains, respectively. In this study, molecular dynamics, docking, and steered molecular dynamics simulations were used to compare the binding and dissociation mechanisms of sLe(x) with mouse and human E-selectin. First, a mouse E-selectin homology model was generated using the human E-selectin crystal structure as a template.ResultsMouse E-selectin was found to have a greater interdomain angle, which has been previously shown to correlate with stronger binding among selectins. sLe(x) was docked onto human and mouse E-selectin, and the mouse complex was found to have a higher free energy of binding and a lower dissociation constant, suggesting stronger binding. The mouse complex had higher flexibility in a few key residues. Finally, steered molecular dynamics was used to dissociate the complexes at force loading rates of 2000-5000 pm/ps(2). The mouse complex took longer to dissociate at every force loading rate and the difference was statistically significant at 3000 pm/ps(2). When sLe(x)-coated microspheres were perfused through microtubes coated with human or mouse E-selectin, the particles rolled more slowly on mouse E-selectin.ConclusionsBoth molecular dynamics simulations and microsphere adhesion experiments show that mouse E-selectin protein binds more strongly to sialyl Lewis x ligand than human E-selectin. This difference was explained by a greater interdomain angle for mouse E-selectin, and greater flexibility in key residues. Future work could introduce similar amino acid substitutions into the human E-selectin sequence to further modulate adhesion behavior.

Project description:BackgroundLewis antigens such as Sialyl Lewis A (sLeA), Sialyl Lewis X (sLeX), Lewis X (LeX), and Lewis Y (LeY) are a class of carbohydrate molecules that are known to mediate adhesion between tumor cells and endothelium by interacting with its selectin ligands. However, their potential role in miscarriage remains enigmatic. This study aims to analyze the expression pattern of sLeA, sLeX, LeX, and LeY in the placental villi tissue of patients with a medical history of unexplained miscarriages.MethodsParaffin-embedded slides originating from placental tissue were collected from patients experiencing a miscarriage early in their pregnancy (6-13 weeks). Tissues collected from spontaneous (n = 20) and recurrent (n = 15) miscarriages were analyzed using immunohistochemical and immunofluorescent staining. Specimens obtained from legally terminated normal pregnancies were considered as control group (n = 18). Assessment of villous vessel density was performed in another cohort (n = 10 each group) of gestation ages-paired placenta tissue. Protein expression was evaluated with Immunoreactive Score (IRS). Statistical analysis was performed by using Graphpad Prism 8.ResultsExpression of sLeA, sLeX, LeX, and LeY in the syncytiotrophoblast was significantly upregulated in the control group compared with spontaneous and recurrent miscarriage groups. However, no prominent differences between spontaneous and recurrent miscarriage groups were identified. Potential key modulators ST3GAL6 and NEU1 were found to be significantly downregulated in the recurrent miscarriage group and upregulated in the spontaneous group, respectively. Interestingly, LeX and LeY expression was also detected in the endothelial cells of villous vessels in the control group but no significant expression in miscarriage groups. Furthermore, assessment of villous vessel density using CD31 found significantly diminished vessels in all size groups of villi (small villi <200 µm, P = 0.0371; middle villi between 200 and 400 µm, P = 0.0010 and large villi >400 µm, P = 0.0003). Immunofluorescent double staining also indicated the co-localization of LeX/Y and CD31.ConclusionsThe expression of four mentioned carbohydrate Lewis antigens and their potential modulators, ST3GAL6 and NEU1, in the placenta of patients with miscarriages was significantly different from the normal pregnancy. For the first time, their expression pattern in the placenta was illustrated, which might shed light on a novel understanding of Lewis antigens' role in the pathogenesis of miscarriages.

Project description:The formation of distant metastasis resulting from vascular dissemination is one of the leading causes of mortality in non?small cell lung cancer (NSCLC). This metastatic dissemination initiates with the adhesion of circulating cancer cells to the endothelium. The minimal requirement for the binding of leukocytes to endothelial E?selectins and subsequent transmigration is the epitope of the fucosylated glycan, sialyl Lewis x (sLex), attached to specific cell surface glycoproteins. sLex and its isomer sialyl Lewis a (sLea) have been described in NSCLC, but their functional role in cancer cell adhesion to endothelium is still poorly understood. In this study, it was hypothesised that, similarly to leukocytes, sLe glycans play a role in NSCLC cell adhesion to E?selectins. To assess this, paired tumour and normal lung tissue samples from 18 NSCLC patients were analyzed. Immunoblotting and immunohistochemistry assays demonstrated that tumour tissues exhibited significantly stronger reactivity with anti?sLex/sLea antibody and E?selectin chimera than normal tissues (2.2? and 1.8?fold higher, respectively), as well as a higher immunoreactive score. High sLex/sLea expression was associated with bone metastasis. The overall ?1,3?fucosyltransferase (FUT) activity was increased in tumour tissues, along with the mRNA levels of FUT3, FUT6 and FUT7, whereas FUT4 mRNA expression was decreased. The expression of E?selectin ligands exhibited a weak but significant correlation with the FUT3/FUT4 and FUT7/FUT4 ratios. Additionally, carcinoembryonic antigen (CEA) was identified in only 8 of the 18 tumour tissues; CEA?positive tissues exhibited significantly increased sLex/sLea expression. Tumour tissue areas expressing CEA also expressed sLex/sLea and showed reactivity to E?selectin. Blot rolling assays further demonstrated that CEA immunoprecipitates exhibited sustained adhesive interactions with E?selectin?expressing cells, suggesting CEA acts as a functional protein scaffold for E?selectin ligands in NSCLC. In conclusion, this work provides the first demonstration that sLex/sLea are increased in primary NSCLC due to increased ?1,3?FUT activity. sLex/sLea is carried by CEA and confers the ability for NSCLC cells to bind E?selectins, and is potentially associated with bone metastasis. This study contributes to identifying potential future diagnostic/prognostic biomarkers and therapeutic targets for lung cancer.

Dataset Information

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers.

Publications

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers.

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