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Interaction of the Oncofetal Thomsen-Friedenreich Antigen with Galectins in Cancer Progression and Metastasis.

ABSTRACT: Aberrant glycosylation of cell membrane proteins is a universal feature of cancer cells. One of the most common glycosylation changes in epithelial cancer is the increased occurrence of the oncofetal Thomsen-Friedenreich disaccharide Gal?1-3GalNAc (T or TF antigen), which appears in about 90% of cancers but is rarely seen in normal epithelium. Over the past few years, increasing evidence has revealed that the increased appearance of TF antigen on cancer cell surface plays an active role in promoting cancer progression and metastasis by interaction with the ?-galactoside-binding proteins, galectins, which themselves are also frequently overexpressed in cancer and pre-cancerous conditions. This review summarizes the current understanding of the molecular mechanism of the increased TF occurrence in cancer, the structural nature, and biological impact of TF interaction with galectins, in particular galectin-1 and -3, on cancer progression and metastasis.

SUBMITTER: Sindrewicz P

PROVIDER: S-EPMC4814717 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Interaction of the Oncofetal Thomsen-Friedenreich Antigen with Galectins in Cancer Progression and Metastasis.

Sindrewicz Paulina P Lian Lu-Yun LY Yu Lu-Gang LG

Frontiers in oncology 20160331

Aberrant glycosylation of cell membrane proteins is a universal feature of cancer cells. One of the most common glycosylation changes in epithelial cancer is the increased occurrence of the oncofetal Thomsen-Friedenreich disaccharide Galβ1-3GalNAc (T or TF antigen), which appears in about 90% of cancers but is rarely seen in normal epithelium. Over the past few years, increasing evidence has revealed that the increased appearance of TF antigen on cancer cell surface plays an active role in promo ...[more]

PMID: 27066458

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Structural basis for distinct binding properties of the human galectins to Thomsen-Friedenreich antigen.

Project description:The Thomsen-Friedenreich (TF or T) antigen, Galβ1-3GalNAcα1-O-Ser/Thr, is the core 1 structure of O-linked mucin type glycans appearing in tumor-associated glycosylation. The TF antigen occurs in about 90% of human cancer cells and is a potential ligand for the human endogenous galectins. It has been reported that human galectin-1 (Gal-1) and galectin-3 (Gal-3) can perform their cancer-related functions via specifically recognizing TF antigen. However, the detailed binding properties have not been clarified and structurally characterized. In this work, first we identified the distinct TF-binding abilities of Gal-1 and Gal-3. The affinity to TF antigen for Gal-3 is two orders of magnitude higher than that for Gal-1. The structures of Gal-3 carbohydrate recognition domain (CRD) complexed with TF antigen and derivatives, TFN and GM1, were then determined. These structures show a unique Glu-water-Arg-water motif-based mode as previously observed in the mushroom galectin AAL. The observation demonstrates that this recognition mode is commonly adopted by TF-binding galectins, either as endogenous or exogenous ones. The detailed structural comparisons between Gal-1 and Gal-3 CRD and mutagenesis experiments reveal that a pentad residue motif ((51)AHGDA(55)) at the loop (g1-L4) connecting β-strands 4 and 5 of Gal-1 produces a serious steric hindrance for TF binding. This motif is the main structural basis for Gal-1 with the low affinity to TF antigen. These findings provide the intrinsic structural elements for regulating the TF-binding activity of Gal-1 in some special conditions and also show certain target and approach for mediating some tumor-related bioactivities of human galectins.

| S-EPMC3176802 | biostudies-literature

Multifunctional nanobeacon for imaging Thomsen-Friedenreich antigen-associated colorectal cancer.

Project description:This research aimed to validate the specificity of the newly developed nanobeacon for imaging the Thomsen-Friedenreich (TF) antigen, a potential biomarker of colorectal cancer. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a Coumarin 6 dye. The surface of the nanosphere was modified with peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-?(1-3)GalNAc with high affinity while the latter enhances the specificity of PNA for the carbohydrates. The specificity of the nanobeacon was evaluated in human colorectal cancer cells and specimens, and the data were compared with immunohistochemical staining and flow cytometric analysis. Additionally, distribution of the nanobeacon in vivo was assessed using an "intestinal loop" mouse model. Quantitative analysis of the data indicated that approximately 2 ?g of PNA were detected for each milligram of the nanobeacon. The nanobeacon specifically reported colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA. Removal of TF from human colorectal cancer cells and tissues resulted in a loss of fluorescence signal, which suggests the specificity of the probe. Most importantly, the probe was not absorbed systematically in the large intestine upon topical application. As a result, no registered toxicity was associated with the probe. These data demonstrate the potential use of this novel nanobeacon for imaging the TF antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer at the molecular level.

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Expression of Thomsen-Friedenreich Antigen in Colorectal Cancer and Association with Microsatellite Instability.

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Fluorescence-based endoscopic imaging of Thomsen-Friedenreich antigen to improve early detection of colorectal cancer.

Project description:Thomsen-Friedenreich (TF) antigen belongs to the mucin-type tumor-associated carbohydrate antigen. Notably, TF antigen is overexpressed in colorectal cancer (CRC) but is rarely expressed in normal colonic tissue. Increased TF antigen expression is associated with tumor invasion and metastasis. In this study, we sought to validate a novel nanobeacon for imaging TF-associated CRC in a preclinical animal model. We developed and characterized the nanobeacon for use with fluorescence colonoscopy. In vivo imaging was performed on an orthotopic rat model of CRC. Both white light and fluorescence colonoscopy methods were utilized to establish the ratio-imaging index for the probe. The nanobeacon exhibited specificity for TF-associated cancer. Fluorescence colonoscopy using the probe can detect lesions at the stage which is not readily confirmed by conventional visualization methods. Further, the probe can report the dynamic change of TF expression as tumor regresses during chemotherapy. Data from this study suggests that fluorescence colonoscopy can improve early CRC detection. Supplemented by the established ratio-imaging index, the probe can be used not only for early detection, but also for reporting tumor response during chemotherapy. Furthermore, since the data obtained through in vivo imaging confirmed that the probe was not absorbed by the colonic mucosa, no registered toxicity is associated with this nanobeacon. Taken together, these data demonstrate the potential of this novel probe for imaging TF antigen as a biomarker for the early detection and prediction of the progression of CRC at the molecular level.

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A One-Step Chemoenzymatic Labeling Strategy for Probing Sialylated Thomsen-Friedenreich Antigen.

Project description:Abnormal expression of sialylated Thomsen-Friedenreich antigen (Neu5Acα2-3Galβ1-3GalNAcα-O-Ser/Thr, sialyl-T) has a strong relationship with various types of human cancers and many other diseases. However, the size and structural complexity, and relatively lower abundance of sialyl-T have posed a significant challenge to its detection. Therefore, details about the role of sialyl-T in a variety of physiological and pathological processes are still poorly understood. Here, a one-step chemoenzymatic labeling strategy to probe sialyl-T is described. This approach enables the sensitive, selective, and rapid detection of sialyl-T, and global profiling and identification of unknown sialyl-T-attached glycoproteins, which are potential therapeutic targets or biomarkers. The use of one-step labeling strategy not only has a higher sensitivity than a typical two-step reporter strategy but also avoids undergoing an additional chemical reaction step to introduce a reporter group after the labeling reaction, making it particularly useful for detecting low-abundance glycan epitopes on living cells.

| S-EPMC5920613 | biostudies-literature

The Thomsen-Friedenreich Antigen: A Highly Sensitive and Specific Predictor of Microsatellite Instability in Gastric Cancer.

Project description:Microsatellite instability (MSI) is a distinct molecular subtype of gastric cancer. In recent years, the clinical consequences of MSI and the therapeutic opportunities to target this peculiar cancer subtype became evident. However, despite the importance of MSI for the stratification of patients, the time and resources required for diagnosis still present an obstacle. In an attempt to identify a new marker for MSI in gastric cancer, we evaluated the expression of five cancer-associated glycan epitopes in a cohort of 13 MSI and 17 microsatellite stable (MSS) cases. Our analysis revealed a highly significant (p < 0.001) association between the expression of the Thomsen-Friedenreich (TF) antigen and MSI status. Hence, we present here the identification of the first single marker for MSI in gastric cancer, excelling with a specificity of 94% (16/17), sensitivity of 69.2% (9/13), negative predictive value of 80% (16/20), and positive predictive value of 90% (9/10). The TF antigen, detected by simple antibody-based assays, is highly specific for carcinoma being undetectable in gastric healthy and premalignant epithelia. This finding lays the basis for new studies and holds promise in improving the rapid identification of MSI in the clinical setting.

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Varied presentation of the Thomsen-Friedenreich disaccharide tumor-associated carbohydrate antigen on gold nanoparticles.

Project description:Three-dimensional self-assembled monolayers of gold coated with the Thomsen-Friedenreich antigen (TF(ag)) disaccharide (beta-Galp-(1-->3)-GalpNAc) in a variety of presentations have been prepared and characterized. Anomalies in the size distribution of our originally synthesized TF(ag)-bearing nanoparticles as shown in dynamic light scattering experiments prompted us to explore the effect of antigen density on the uniformity of the particles. Gold nanoparticles containing a range of densities 'diluted' with copies of the PEG-thiol spacer unit showed that lower antigen density affords more uniform particles. We also wanted to study the constitution of the actual antigen by synthesizing nanoparticles not only with the linker-extended disaccharide, but also within the context of the surrounding peptide sequence where it may be presented in vivo. The synthesis of TF(ag)-containing glycopeptide thiols based on a mucin peptide repeating unit were prepared, assembled into gold nanoparticles and their physical properties evaluated. These novel multivalent tools should prove extremely useful in exploring the binding properties and immune response to this important carbohydrate antigen.

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Recognition of the Thomsen-Friedenreich pancarcinoma carbohydrate antigen by a lamprey variable lymphocyte receptor.

Project description:Variable lymphocyte receptors (VLRs) are leucine-rich repeat proteins that mediate adaptive immunity in jawless vertebrates. VLRs were recently shown to recognize glycans, such as the tumor-associated Thomsen-Friedenreich antigen (TF?; Gal?1-3GalNAc?), with a selectivity rivaling or exceeding that of lectins and antibodies. To understand the basis for TF? recognition by one such VLR (VLRB.aGPA.23), we measured thermodynamic parameters for the binding interaction and determined the structure of the VLRB.aGPA.23-TF? complex to 2.2 ? resolution. In the structure, four tryptophan residues form a tight hydrophobic cage encasing the TF? disaccharide that completely excludes buried water molecules. This cage together with hydrogen bonding of sugar hydroxyls to polar side chains explains the exquisite selectivity of VLRB.aGPA.23. The topology of the glycan-binding site of VLRB.aGPA.23 differs markedly from those of lectins or antibodies, which typically consist of long, convex grooves for accommodating the oligosaccharide. Instead, the TF? disaccharide is sandwiched between a variable loop and the concave surface of the VLR formed by the ?-strands of the leucine-rich repeat modules. Longer oligosaccharides are predicted to extend perpendicularly across the ?-strands, requiring them to bend to match the concavity of the VLR solenoid.

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Sialylation of Thomsen-Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy.

Project description:AIM:The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status of blood-based glycans as potential disease markers. METHODS:We employed immunoblotting, lectin histochemistry and mass spectrometry. RESULTS:GNE myopathy muscle showed hyposialylation of predominantly O-linked glycans. The O-linked glycome of patients' plasma compared with controls showed increased amounts of desialylated Thomsen-Friedenreich (T)-antigen, and/or decreased amounts of its sialylated form, ST-antigen. Importantly, all patients had increased T/ST ratios compared with controls. These ratios were normalized in a patient treated with intravenous immunoglobulins as a source of sialic acid. DISCUSSION: GNE myopathy clinical trial data will reveal whether T/ST ratios correlate to muscle function. CONCLUSION:Plasma T/ST ratios are a robust blood-based biomarker for GNE myopathy, and may also help explain the pathology and course of the disease.

| S-EPMC4160177 | biostudies-literature

Synthesis of the Thomsen-Friedenreich-antigen (TF-antigen) and binding of Galectin-3 to TF-antigen presenting neo-glycoproteins.

Project description:The Thomsen-Friedenreich-antigen, Gal(β1-3)GalNAc(α1-O-Ser/Thr (TF-antigen), is presented on the surface of most human cancer cell types. Its interaction with galectin 1 and galectin 3 leads to tumor cell aggregation and promotes cancer metastasis and T-cell apoptosis in epithelial tissue. To further explore multivalent binding between the TF-antigen and galectin-3, the TF-antigen was enzymatically synthesized in high yields with GalNAc(α1-EG3-azide as the acceptor substrate by use of the glycosynthase BgaC/Glu233Gly. Subsequently, it was coupled to alkynyl-functionalized bovine serum albumin via a copper(I)-catalyzed alkyne-azide cycloaddition. This procedure yielded neo-glycoproteins with tunable glycan multivalency for binding studies. Glycan densities between 2 and 53 glycan residues per protein molecule were obtained by regulated alkynyl-modification of the lysine residues of BSA. The number of coupled glycans was quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a trinitrobenzene sulfonic acid assay. The binding efficiency of the neo-glycoproteins with human galectin-3 and the effect of multivalency was investigated and assessed using an enzyme-linked lectin assay. Immobilized neo-glycoproteins of all modification densities showed binding of Gal-3 with increasing glycan density. However, multivalent glycan presentation did not result in a higher binding affinity. In contrast, inhibition of Gal-3 binding to asialofetuin was effective. The relative inhibitory potency was increased by a factor of 142 for neo-glycoproteins displaying 10 glycans/protein in contrast to highly decorated inhibitors with only 2-fold increase. In summary, the functionality of BSA-based neo-glycoproteins presenting the TF-antigen as multivalent inhibitors for Gal-3 was demonstrated.

| S-EPMC7329766 | biostudies-literature

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