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Involvement of fucosylated antigens in different aspects of cancer progression. Due to genetic or epigenetic alterations, overexpression of certain fucosyltransferases (FUTs) by cancer cells leads to increased cell-surface expression of fucosylated Lewis antigens. Aberrant regulation of the fucosylation machinery in cancer cells is causally associated with the acquisition of various tumorigenic properties, such as increased cell survival and proliferation, epithelial to mesenchymal transition, metastasis, resistance to chemotherapy, and cancer stemness. In parallel, interaction of cancer cells overexpressing Lewis antigens with endothelial or immune cells bearing Lewis antigen-specific receptors might also play a critical role during cancer-induced angiogenesis and immunosuppression, respectively.
Source publication
Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewisa, Lewisb, and sialyl Lewisa) and type II (H2, Lewisx, Lewisy, and sialyl Lewisx) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated ex...
Citations
... In cancer, these FUT enzymes play a role in the biosynthesis of tumour antigens such as simple (Le a and Le b ) or sialylated (sLe a and sLe b ) Lewis (Le) structures [54]. In melanoma, the expression of FUT1 and FUT4 is higher in cell lines derived from metastases when compared to primary tumours [37]. ...
Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour ‘glycocode’ plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti‐tumour defence through interactions with lectins on immune cells, which are crucial to shape anti‐tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan‐based strategies aiming at restoring a functional anti‐tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti‐tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy.
... H-type-II glycotope Fucosylation is altered in in amed and cancer tissues [75,76,90]. Glycoconjugates containing α-Fuc participate in diverse interactions between cells and ECM [105][106][107], and the change in their expression correlates with tumor growth, invasion, and metastasis [95,[107][108][109][110][111][112][113]. The aberrant fucosylation is mainly attributed to upregulation of fucosyltransferases (FUTs) and downregulation of α-L-fucosidases (FUCAs), promoting in ammatory conditions and malignancy [19-21, 105, 108, 113-115]. ...
... Furthermore, in addition to Le Y and Le B , the PTC carcinomas also show stronger immunoreactivity to other fucosylated or sialofucosylated forms of Lewis antigens (Le A , Le X , sLe A and sLe X ) [64, 96-101, 120, 121], which carry α1,3-Fuc or α1,4-Fuc added on GlcNAc by FUT3-FUT7 or FUT9 [127]. The ectopic expression of sLe A and sLe X (normally expressed by leukocytes) by several cancers is associated with malignancy [113]. The number of Lewis positive cases has been higher in PTC than in FTC carcinomas [98, 120,121]. ...
Galactia lindenii lectin type-II (GLL-II) belongs to the group of the legume lectins. The present study investigated the GLL-II staining patterns in histological sections of neoplastic and non-neoplastic thyroid tissues. Besides, hemagglutination assays (HA) using the GLL-II on red blood cells (RBCs) of different glycomic profile were performed, complementing previous results. The differential staining in Papillary Thyroid Cancer (PTC), Invasive Encapsulated Follicular Variant Papillary Thyroid Carcinoma (IEFV-PTC), Hashimoto's thyroiditis (HT), and non-neoplastic thyroid with goiter changes, together with the HA results and along with reviewed glycoprofiles of unhealthy conditions in other organs, allowed us to propose the potential utility of GLL-II in lectin platforms used to discriminate human pathological samples from normal ones. The present study shed light on potential applications of GLL-II in determining alterations of glycosylation patterns in specific cells, tissues, or body fluids, as well as glycotopes biomarkers of healthy or pathological conditions.
... It has many biologically relevant functions as involvement in ABO and Lewis x blood group systems (de Mattos, 2016;Mondal et al., 2018); leukocyte extravasation (Nimrichter et al., 2008); fertilization (Pang et al., 2011); development, particularly neural development (Fenderson et al., 1990;Ohata et al., 2009); immunological modulation (Marth & Grewal, 2008); cancer metastasis (Blanas et al., 2018;Keeley et al., 2019); inflammation (Li et al., 2014;Thompson et al., 1989); and cognitive processes (Mountford et al., 2015;Tosh et al., 2019). ...
Background
FCSK ‐congenital disorder of glycosylation (FCSK‐CDG) is a recently discovered rare autosomal recessive genetic disorder with defective fucosylation due to mutations in the fucokinase encoding gene, FCSK . Despite the essential role of fucokinase in the fucose salvage pathway and severe multisystem manifestations of FCSK‐CDG patients, it is not elucidated which cells or which types of fucosylation are affected by its deficiency.
Methods
In this study, CRISPR/Cas9 was employed to construct an FCSK‐CDG cell model and explore the molecular mechanisms of the disease by lectin flow cytometry and real‐time PCR analyses.
Results
Comparison of cellular fucosylation by lectin flow cytometry in the created CRISPR/Cas9 FCSK knockout and the same unedited cell lines showed no significant change in the amount of cell surface fucosylated glycans, which is consistent with the only documented previous study on different cell types. It suggests a probable effect of this disease on secretory glycoproteins. Investigating O‐fucosylation by analysis of the NOTCH3 gene expression as a potential target revealed a significant decrease in the FCSK knockout cells compared with the same unedited ones, proving the effect of fucokinase deficiency on EGF‐like repeats O‐fucosylation.
Conclusion
This study expands insight into the FCSK‐CDG molecular mechanism; to the best of our knowledge, it is the first research conducted to reveal a gene whose expression level alters due to this disease.
... 46 Furthermore, increased expression of these glycan epitopes can also in uence various aspects of cancer cell biology, including epithelial-mesenchymal transition, immune interactions, induction of multidrug resistance, and cancer stemness. 47 However, further investigation is necessary to fully elucidate the speci c mechanisms and downstream effects of sulfated N-glycans on BC progression and invasion. Moreover, focusing on these N-glycan pathways may offer a promising therapeutic approach for BC. 4 In particular, targeting the sulfotransferase enzyme responsible for synthesizing speci c sulfated N-glycans may impede BC progression and metastasis. ...
Background
Breast cancer (BC) is a significant global health concern among women, and early detection plays a pivotal role in enhancing patient survival rates. Alterations in the structure and abundance of sulfated glycans have been linked to various diseases including cancer. However, due to their low abundance, analyzing sulfated glycans poses challenges, making the investigation of sulfated glycan profiles a topic of significant interest in the search for novel biomarkers for early BC detection.
Methods
In this study, we utilized a glycoblotting-based sulphoglycomic workflow to examine the presence of sulfated N-glycans in the serum of Ethiopian patients with BC. This approach integrates high-throughput glycoblotting enrichment technology, WAX separation, and MALDI-TOF MS. The sulfated N-glycan profiles in the whole serum of 76 BC patients and 20 age-matched healthy controls were analyzed.
Results
The findings revealed that seven monosulfated glycans were significantly upregulated in the serum of BC patients compared to that in the control group. Each identified glycan showed significant abundance with an AUC ≥ 0.8 and demonstrated high diagnostic accuracy in predicting early-stage BC patients. Sulfated glycans abundantly displayed terminal Lewis-type glycan epitopes, unlike their negligible presence in nonsulfated N-glycans in serum, whose abundance has been strongly associated with BC progression, metastasis, and immune invasion. Importantly, sulfated glycans were analyzed without removing the sialic group, allowing for a comprehensive evaluation of the sialylation status of the identified sulfated glycans.
Conclusion
To the best of our knowledge, this study represents the first quantitative analysis of sulfated N-glycans in patients with BC, identifying novel glyco-biomarkers with discriminatory potential in the early stages of BC.
... As the responsible gene for fucosylation, fucosyltransfereases such as FUT6 mediate α1-3 fucosylation while FUT3 mediates α1-3/4 fucosylation [26], playing a role as key enzymes for sialyl-Lewis X and/or CA19-9 generation [1,[31][32][33][34]. Our data demonstrated that KRAS mutants were hyper-α1-3/4 fucosylated and, at the same time, FUT6 and FUT3 RNA expression was actually elevated in our KRAS mutant organoids. ...
Aberrant glycosylation in tumor cells is a hallmark during carcinogenesis. KRAS gene mutations are the most well-known oncogenic abnormalities but their association with glycan alterations in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. We employed patient-derived 3D organoids to culture pure live PDAC cells, excluding contamination by fibroblasts and immune cells, to gasp the comprehensive cancer cell surface glycan expression profile using lectin microarray and transcriptomic analyses. Surgical specimens from 24 PDAC patients were digested and embedded into a 3D culture system. Surface-bound glycans of 3D organoids were analyzed by high-density, 96-lectin microarrays. KRAS mutation status and expression of various glycosyltransferases were analyzed by RNA-seq. We successfully established 16 3D organoids: 14 PDAC, 1 intraductal papillary mucinous neoplasm (IPMN), and 1 normal pancreatic duct. KRAS was mutated in 13 (7 G12V, 5 G12D, 1 Q61L) and wild in 3 organoids (1 normal duct, 1 IPMN, 1 PDAC). Lectin reactivity of AAL (Aleuria aurantia) and AOL (Aspergillus oryzae) with binding activity to α1-3 fucose was higher in organoids with KRAS mutants than those with KRAS wild-type. FUT6 (α1-3fucosyltransferase 6) and FUT3 (α1-3/4 fucosyltransferase 3) expression was also higher in KRAS mutants than wild-type. Meanwhile, mannose-binding lectin (rRSL [Ralstonia solanacearum] and rBC2LA [Burkholderia cenocepacia]) signals were higher while those of galactose-binding lectins (rGal3C and rCGL2) were lower in the KRAS mutants. We demonstrated here that PDAC 3D-cultured organoids with KRAS mutations were dominantly covered in increased fucosylated glycans, pointing towards novel treatment targets and/or tumor markers.
... The excessive expression and immature biosynthesis of Tn, sTn, and T antigens, resulting from abnormal Oglycosylation, promote tumor metastasis. 22 Since these structures are not found in standard cell glycoproteins, they offer the potential for identifying molecular differences between cancerous and healthy cells. Given that glycoproteins are secreted into the bloodstream or other body fluids, they present a viable option for non-invasive diagnostic methods ( Figure 1). ...
Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide and is a leading cause of cancer-related mortality. Since many colon cancers present no significant clinical symptoms, identifying new biomarkers or a set of biological indicators significant for clinical trials is crucial for the early detection of CRC. This advancement also aids in establishing new objectives for interventional therapeutic strategies against the disease. Currently, research is exploring various proteins, glycoproteins, and cellular and humoral substances involved in cellular homeostasis mechanisms as potential cancer markers. This review examines the potential utility of fucosylation and sialylation processes, as well as sex hormones, as biomarkers in the diagnosis and prognosis of CRC. A comprehensive search was conducted in PUBMED, MEDLINE, and Google Scholar, supplemented by a manual search of relevant journals. The keywords were L-fucose, sialic acid, fucosyltransferase-4, galectin-3, and steroid hormones in CRCs.
... Langerin exhibits affinity for blood group antigens A and B (Feinberg et al. 2011), as well as sulfated and mannosylated glycans, keratan sulfate (Tateno et al. 2010) and beta-glucans (de Jong et al. 2010). SRCL demonstrates binding capability to Lewis structures X and A (Blanas et al. 2018) as well as various carbohydrates, including Gal-type ligands, D-galactose, L-and D-fucose, GalNAc, and T/Tn antigens, in a calcium-dependent manner (Yoshida et al. 2003). LSECtin exhibits high selectivity for glycoproteins terminating in GlcNAcβ1-2Man (Powlesland et al. 2008) and recognizes a pair of positional glycan isomers (LDN3 and LDN6), along with a nonelongated GlcNAc4Man3 N-glycan (Bertuzzi et al. 2022). ...
Glycosylation is a prominent posttranslational modification, and alterations in glycosylation are a hallmark of cancer. Glycan-binding receptors, primarily expressed on immune cells, play a central role in glycan recognition and immune response. Here, we used the recombinant C-type glycan-binding receptors CD301, Langerin, SRCL, LSECtin, and DC-SIGNR to recognize their ligands on tissue microarrays (TMA) of a large cohort (n = 1859) of invasive breast cancer of different histopathological types to systematically determine the relevance of altered glycosylation in breast cancer. Staining frequencies of cancer cells were quantified in an unbiased manner by a computer-based algorithm. CD301 showed the highest overall staining frequency (40%), followed by LSECtin (16%), Langerin (4%) and DC-SIGNR (0.5%). By Kaplan–Meier analyses, we identified LSECtin and CD301 as prognostic markers in different breast cancer subtypes. Positivity for LSECtin was associated with inferior disease-free survival in all cases, particularly in estrogen receptor positive (ER+) breast cancer of higher histological grade. In triple negative breast cancer, positivity for CD301 correlated with a worse prognosis. Based on public RNA single-cell sequencing data of human breast cancer infiltrating immune cells, we found CLEC10A (CD301) and CLEC4G (LSECtin) exclusively expressed in distinct subpopulations, particularly in dendritic cells and macrophages, indicating that specific changes in glycosylation may play a significant role in breast cancer immune response and progression.
... The single cell transcriptomic analysis shows that only quiescent CD44 high T-ALL cells possess FUT7 expression (data not shown), which participates to the sLe x motif creation and allows the E-selectin binding for the Ki67 neg/low CD44 high LSC population. On note, other studies have shown that FUTs expression may be a prognostic marker associated with bad clinical outcomes in different tumors[51][52][53][54][55] . ...
T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by an increased proliferation and incomplete maturation of T-cell progenitors. Despite therapeutic improvements, relapses are often of bad prognosis. Therapeutic vulnerabilities and chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment remain an important field of investigation. Employing single cell RNA sequencing (scRNAseq) of human T-ALL cells recovered from adipocyte-rich and -poor BM, a distinct leukemic stem cell (LSC) population defined by quiescence and elevated CD44 level (Ki67neg/lowCD44high) expression is identified in both territories. In vivo chemotherapy demonstrated that the LSC population evades drug treatment. Patient sample analyses confirmed the presence of Ki67neg/lowCD44high LSC both at diagnosis and relapse that displayed a specific transcriptomic signature. Interestingly, the intense expression of CD44 in T-ALL Ki67neg/lowLSC was associated with E-selectin binding. Importantly, when 39 human T-ALL samples were analyzed, the E-selectin binding ability was found significantly higher in Relapse/Refractory compared to drug-sensitive patients. These findings characterize a T-ALL LSC population with chemoresistant properties and shade light on new strategies for prognostic stratification while opening avenues for novel therapeutic options.
... In addition, there are some shared carbohydrate antigens between N-glycosylation and O-glycosylation. For example, the typical tumour-associated antigens sialyl Lewis a (NeuAcα2-3Galβ1-3 [Fucα1-4] GlcNAc, SLe a ) and SLe x , which can appear on both N-glycans and O-glycans [39]. ...
Mucin glycans are important component of the mucus barrier and vital defence against physical and chemical damage as well as pathogens. Abnormal expression of mucin glycans can lead to disease, especially cancer. Here, we first summarize the main types of glycosylation on mucins and the mechanisms by which abnormal mucin glycans occur. We next describe the role of ab-normal mucin glycans in cancer. Finally, we describe MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example.
... These fucosylated carbohydrate moieties play a crucial role in regulating various biological processes within cells, including cell survival, adhesion, cellular signaling and function, and cell-to-cell or cell-to-environment interactions. In effect, recent research has revealed that altered fucosylation in cells and tissues is associated with a number of diseases, ranging from inflammatory conditions such as collagen-induced arthritis (2), rheumatoid arthritis (3,4), allergic airway inflammation (5), bacterial intestinal inflammation (6) and dry eye disease (7) to multiple types of cancers (8). ...
Fucosylation plays a critical role in cell-to-cell interactions and disease progression. However, the effects of fucosylation on splenocytes and their interactions with T cells remain unclear. In this study, we aimed to explore the transcriptome profiles of splenocytes deficient in fucosyltransferase (FUT) 1, an enzyme that mediates fucosylation, and investigate their impact on the proliferation and differentiation of T cells. We analyzed and compared the transcriptomes of splenocytes isolated from Fut1 knockout (KO) mice and those from wild-type (WT) mice using RNA-seq. Additionally, we examined the effects of Fut1 KO splenocytes on CD4 T cell proliferation and differentiation, in comparison to WT splenocytes, and elucidated the mechanisms involved. The comparative analysis of transcriptomes between Fut1 KO and WT splenocytes revealed that thrombospondin (THBS)-1, among the genes related to immune response and inflammation, was the most highly downregulated gene in Fut1 KO splenocytes. The reduced expression of THBS1 was further confirmed using qRT-PCR and flow cytometry. In coculture experiments, Fut1 KO splenocytes promoted the proliferation of CD4 T cells and drove their differentiation towards Th1 and Th17 cells, compared to WT splenocytes. Moreover, the levels of IL-2, IFN-γ and IL-17 were increased, while IL-10 was decreased, in T cells cocultured with Fut1 KO splenocytes compared to those with WT splenocytes. These effects of Fut1 KO splenocytes on T cells were reversed when THBS1 was replenished. Taken together, our results demonstrate that splenocytes with Fut1 deficiency promote CD4 T cell proliferation and Th1/Th17 differentiation at least in part through THBS1 downregulation.
