[Frontiers in Bioscience 17, 670-699, January 1, 2012]

Mechanisms of cancer-associated glycosylation changes

Fabio Dall'Olio1, Nadia Malagolini1, Marco Trinchera2, Mariella Chiricolo1

1Department of Experimental Pathology, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy, 2Department of Biomedical Sciences Experimental and Clinical (DSBSC), University of Insubria, Via J.H. Dunant 5, 21100 Varese, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Survey of cancer-associated glycosylation changes
3.1. b1,6 branching
3.2. Sialyl Lewis antigens
3.3. a2,6-sialylated lactosamine (Sia6LacNAc)
3.4. T, Tn and sialyl-Tn antigens
3.5. Gangliosides
4. Mechanisms leading to altered glycan structures
4.1. Altered glycosidase expression
4.2. Masking of sugar structures by substituent groups
4.3. Altered expression of sugar and sugar nucleotide transporters
4.4. Competition between normal and cancer-associated carbohydrate structures
5. Mechanisms of regulation of glycogenes
5.1. Regulation of glycogenes by oncogenes and tumor suppressor genes
5.2. Glycosylation changes and hypoxia
5.3. Epigenetic regulation
6. Perspective
7. Acknowledgements
8. References

1. ABSTRACT

Cell membrane glycoconjugates undergo characteristic changes as a consequence of neoplastic transformation. The cancer-associated carbohydrate structures play key roles in cancer progression by altering the cell-cell and cell-environment interactions. In this review, we will discuss some of the most relevant cancer-associated carbohydrate structures, including the b1,6-branching of N-linked chains, the sialyl Lewis antigens, the a2,6-sialylated lactosamine, the Thomsen-Friedenreich-related antigens and gangliosides. We will describe the mechanisms leading to the expression of these structures and their interactions with sugar binding molecules, such as selectins and galectins. Finally, we will discuss how the glycosylation machinery of the cell is controlled by signal transduction pathways, epigenetic mechanisms and responds to hypoxia.

2. INTRODUCTION

The surface of eukaryotic cells is covered by a sugar coat, known as glycocalix. The carbohydrate molecules forming the glycocalix are either linked to proteins or to lipids. The vast majority of cell membrane or secreted proteins are decorated by sugar chains and are consequently referred to as glycoproteins. The sugar chains linked to glycoproteins are classified in two main types: those linked to the amidic nitrogen of asparagine (referred to as N-linked chains) (1) and those linked to the hydroxyl group of serine or threonine (referred to as O-linked chains) (2). The sugar chains of glycoproteins can play highly specific roles, including the receptor function for microorganisms and toxins and the modulation of the cell-cell and cell-microenvironment interactions (3). In cancer tissues, glycosylation is profoundly altered, leading to the expression of cancer-associated antigens which, in some cases, recapitulate the antigens expressed during fetal life (4, 5). These structures may play fundamental roles in cancer progression through different mechanisms. In this review we will discuss the molecular mechanisms which are at the basis of the expression of some cancer-related carbohydrate structures and the mechanisms through which these structures exert their biological effects. Many of these biological effects are mediated by interactions with animal lectins, in particular selectins, which recognize sialylated Lewis antigens (6-8) and galectins which bind structures terminated by galactose and whose importance in cancer is increasingly recognized (9-15). The identification of the mechanisms of cancer-associated glycosylation changes is crucial in the perspective of therapeutic interventions aimed at the normalization of the glycosylation pattern of cancer cells. Cancer-associated glycosylation changes are in some cases tissue-specific, while in other cases are broadly expressed. In the next section we will focus on some of the broadly expressed cancer-associated carbohydrate structures.

3. SURVEY OF CANCER-ASSOCIATED GLYCOSYLATION CHANGES

3.1. b1,6 branching.

The b1,6 branching of N-linked chains consists in the addition of an antenna whose first GlcNAc is b1,6-linked to a core mannose residue (Figure 1). This antenna, which can be detected by the leukoagglutinin from Phaseolus vulgaris (L-PHA), is preferentially elongated by polylactosaminic sequences and is frequently terminated by antigens of the Lewis type (Figure 1). Although the association of b1,6-branching with metastasis has long been known (16), the conclusive evidence about the causative role played by these structure in metastasis formation came from studies in mice in which the enzyme responsible for this modification, b1,6N-acetylglucosaminyltransferase V, (GnT5 product of the Mgat5 gene), was knocked down (Mgat5-/-). Mice expressing the polyomavirus middle T antigen (PyMT) from a transgene in mammary epithelium, spontaneously develop mammary tumors. When these mice were crossed with Mgat5-/- mice, the tumors grew slower than in the PyMT-transgenic littermate expressing Mgat5 and metastasis formation was almost completely inhibited (17). Cells derived from Mgat5-/- mice exhibited increased contact inhibition and substratum adhesion than Mgat5-expressing cells (18).

The relationship between b1,6-branching and increased growth and metastasis is probably due to more than one mechanism (19). The sugar chains elaborated by GnT5 decorate various cell surface molecules, including growth-promoting receptors (such as PDGFR and EGFR) and receptors with arrest/morphogenic activity (such as TGF-bR and CTLA-4). b1,6-branched, polylactosaminic chains are a preferred ligand for galectin-3 which, consequently, forms a lattice which stabilizes the receptors on the cell surface (19). However, growth-promoting receptors express an average higher number of N-linked glycans (high-n receptors) than receptors with arrest/morphogenic activity (low n-receptors) (20). As a consequence, the galectin-3-mediated stabilization of membrane receptors favors highly-branched, growth promoting receptors. Interestingly, the switch from growth to arrest can be regulated by the nutrient flux. In fact, glucose is converted to glucosamine and UDP N-acetylglucosamine, which is the donor substrate of GlcNAc-transferases. An increase of UDP-GlcNAc levels results in a little change of the glycosylation of high n-receptors but in a dramatic increase of glycosylation (and galectin binding capacity) of low-n receptors. This change mediates the switch from a growth to an arrest condition. Moreover, galectin-3 binding to b1,6-branched glycans regulates tumor cell motility by stimulating focal adhesion remodeling, FAK and PI3K activation, local F-actin instability, and a5b1 integrin translocation to fibrillar adhesions (21).

Another mechanisms proposed to explain the relationship between b1,6-branching and metastasis involves matriptase, an activator of both urokinase-type plasminogen activator and hepatocyte growth factor. This molecule, when glycosylated by GnT5, acquires resistance to degradation and increased activity (22, 23). A direct effect of galectin-3 on VEGF- and bFGF-mediated angiogenesis has been shown by a recent paper showing that this effect is due to the binding of galectin-3 to the b1,6-branched chains of avb3 integrin and to the activation of focal adhesion kinase signaling (24). As discussed in detail in section 5.1, MGAT5 expression is regulated by the Ras pathway, thus explaining its close association with cancer. In many circumstances, GnT5 activity is counteracted by that of a competing enzyme, GnT3 (Figure 1) (section 4.4), which synthesizes bisecting N-linked glycans.

3.2. Sialyl Lewis antigens

Lewis a and Lewis b antigens are originated by the mono- or di- fucosyl substitution of type 1 chains while Lewis x and Lewis y derive from the mono- or di-fucosyl- substitution of type 2 chains (Figure 2). The mono-fucosyl substitution of the a2,3-sialylated type 1 or type 2 chains leads to the formation of sialyl Lewisa (sLea) and sialyl Lewisx (sLex) antigens, respectively (25). These structures are usually present at the terminal non-reducing ends of polylactosaminic chains, preferentially mounted on the b1,6-branching of N-linked chains (Figure 1) or of O-linked chains (26), but also on glycolipids (27). An aberrant expression of Lewis-type antigens appears to be a general cancer-associated phenomenon, reported in carcinomas of the lung (28), colon (27, 29, 30), stomach (31) and kidney (32). The sLea tetrasaccharide is the epitope of CA19-9 antigen, a cancer-associated marker widely used in the clinical practice. The interest in the expression of sialyl Lewis antigens in cancer increased enormously after the discovery that sLex and sLea acted as ligands for E- and P-selectin cell adhesion molecules expressed on activated endothelial cells (6, 33-35). The physiological role of E- and P-selectins is to mediate leukocyte extravasation at sites of tissue damage or injury (36). However, these molecules may also regulate the metastatic cascade by forming emboli of cancer cells and platelets and favoring their arrest on endothelia (7, 37-39). In some cell lines, the major glycoproteins carrying sialyl Lewis antigens have been identified as the hyaluronate receptor CD44 (37, 40, 41), mucin 1 (MUC1) (42-44) and lysosomal membrane glycoproteins 1 and 2 (LAMP-1 and LAMP-2) (44). The relationship between expression of sialylated Lewis antigens and hematogenous metastasis is demonstrated by many clinical and experimental studies (45). In colon cancer patients, increased expression of sLex and sLea antigens correlated with metastasis and poor survival (46-49). sLex correlated with malignancy also in renal cell carcinoma (50) and breast cancer (51, 52), although in the latter the survival did not appear to be related with sLex expression (53).

Several studies have reported that down-regulation of sialyl Lewis antigen expression by knock-down of key glycosyltransferases in cancer cell lines resulted in reduced selectin binding and reduced metastatic ability (54-57), while cancer cells forced to express sialyl Lewis antigens by gene transfer exhibited increased adhesion to selectins in vitro and increased metastatic ability in vivo (58). Consistently, populations of cancer cells selected for their increased metastatic potential often displayed increased expression of sialyl Lewis antigens (59, 60). The role of selectins in the metastatic process was confirmed by the findings that the formation of experimental pulmonary metastases could be inhibited by the use of peptides mimicking sLea and were inhibited in E-selectin- knock-out mice (61).

Apart from the role as selectin ligands, sialyl Lewis antigens can play a role in cancer progression in at least two other key steps of invasion: angiogenesis and immune recognition of cancer cells. The role of sLex in angiogenesis is supported by the finding that when epidermoid cancer cells were co-cultured with endothelial cells, the former produced nests of growing cells surrounded by tube-like networks consisting of endothelial cells. These phenomena could be reproduced in vivo and could be inhibited by antibodies against sLex (62). The ability of sLex-expressing cancer cells to promote angiogenesis was confirmed by the fact that inhibition of sLex biosynthesis in hepatocarcinoma HepG2 cells resulted an impairment of their ability to induce angiogenesis (63). The role of sLex in the recognition of cancer cells by natural killer (NK) cells stemmed from the unexpected observation that melanoma cells expressing high sLex levels were less metastatic than cells expressing moderate levels of the antigen (64, 65). This striking behavior was explained by the finding that high sLex-expressing cells were a better target of NK cells than cells expressing moderate levels of the antigen (65). Altogether, these findings indicate that sialyl Lewis antigens are important in mediating key steps of the metastatic process, in particular the adhesion of emboli of cancer cells to endothelia and neoangiogenesis. Nevertheless, very high expression levels of sLex can trigger a strong NK-mediated tumor rejection.

The terminal steps of the biosynthesis of sialyl Lewis antigens proceeds from the a1,3/4 fucosylation of a2,3-sialylated type 1 (sLea) or type 2 (sLex) chains. On this basis the role of a1,3/4 fucosyltransferases and a2,3 sialyltransferases in the cancer-related over-expression of sialylated Lewis antigens has been the focus of intense investigation. It should be noted that the forced expression or down-regulation of a2,3 sialyltransferases (58, 66) or of a1,3 fucosyltransferases (54, 56) or of core 2 b1,6 N-acetylglucosaminyltransferase (C2GnT, Figure 3) (67) could modulate the expression of sialyl Lewis antigens in experimental systems. However, this does not necessarily imply the regulatory role of each mentioned glycosyltransferase in vivo. There are at least five enzymes which can mediate the addition of fucose in a1,3 linkage to an a2,3-sialylated type 2 chain: fucosyltransferases III, IV, V, VI and VII (Fuc-TIII-Fuc-TVII, products of genes FUT3-FUT7), while only one (Fuc-TIII) can add fucose in a1,4-linkage to an a2,3-sialylated type 1 chain. The expression of sLex appears to be regulated mainly by Fuc-TVI in breast tumors (68), while in lung tumors it is regulated by a coordinate up-regulation of Fuc-TIII and Fuc-TVI (69). On the contrary, in gastrointestinal tumors, such as pancreatic cancer, the over-expression of sialyl Lewis antigens did not correlate with any single glycosyltransferase gene (70). In colon cancer, the molecular basis of the over-expression of sialyl Lewis antigens are particularly complex. An investigation on the level of activity of the fucosyltransferases synthesizing sLea or sLex concluded that an altered activity of fucosyltransferases could not explain the increased expression of sLea/sLex antigens in colon cancer tumors (71). Consistently, other investigations reported that the mRNA level of different fucosyltransferases and sialyltransferases involved in the biosynthesis of sialylated Lewis antigens could not explain their increased expression in colon cancer tissues (72, 73). In a recent paper, we have shown that Fuc-TVI is the major, if not the only, sLex synthase in colorectal cancer tissues and cell lines (74). The activity of this enzyme showed a significant relationship with sLex in cancer tissues, suggesting that terminal a1,3 fucosylation is a limiting step in sLex biosynthesis in colon cancer tissues. However, in agreement with previous studies, we found that Fuc-TVI was not over-expressed in cancer. Thus, the problem of sLex over-expression in cancer remains open. A likely explanation is based on a competition between Fuc-TVI and enzymes synthesizing alternative structures, such as the Sda antigen (75, 76) or the sialyl 6-sulfo Lewisx antigen (77) (Figure 4, section 4.4). However, the biosynthesis of sialyl Lewis antigens is a complex process involving the coordinate expression of several glycosyltransferases, which might be different depending on the nature of the glycoconjugate (N- or O-linked chains of glycoproteins or glycolipids) carrying the antigen. In fact, the expression of both sLex and sLea antigens expressed by glycolipids in colon cancer tissues has been related to the activation of a b1,3GlcNAc transferase which synthesizes a sugar chain which is a precursor for both type 1 and 2 Lewis structures (78). Interestingly, this enzyme is activated by Helicobacter pylori infection, leading in stomach cells to increased expression of sLex ,which is a ligand for H. pylori adhesin SabA (79). On the other hand, the expression of sLex/sLea antigens on O-linked chains of glycoproteins is strongly dependent on C2GnT (26). The relative abundance of type 1 and type 2 chains is an important factor in determining the relative level of expression of sLex/sLea antigens. An up regulation of lactosaminic chains (80) and of their biosynthetic enzymes b1,4-galactosyltransferase I (81) and -IV (82) and a down-regulation of the b1,3-galactosyltransferase which synthesizes type 1 chains in epithelia (b3GalT5) (83, 84), has been reported in colon cancer (85-87), indicating a switch towards the synthesis of type 2 chains in the transformation of colonic tissues. The key role of b3GalT5 in the regulation of the balance between type-1 and -2 chains was also indicated by the finding that suppression by anti-sense DNA of b3GalT5 resulted in down-regulation of sLea and up-regulation of sLex and of lactosaminic chains in the pancreatic cancer cell line BxPC3 (88). The down-regulation of the biosynthesis of type 1 chains in colon cancer tissues leaves unanswered the question on the origin and the nature of the circulating sLea antigen (CA 19.9) present in the blood of several patients affected by various cancers of digestive organs. Recent data identified glycolipids associated with bile globular membrane as another CA 19.9 carrier, other than mucins, in the sera of pancreatic cancer patients (89).

3.3. a2,6-sialylated lactosamine (Sia6LacNAc).

Lactosaminic chains expressed by N- or O-linked chains of the polylactosaminic type are frequently terminated by sialic acid linked either through an a2,3- or an a2,6 bond (Figure 2). a2,6-sialylated lactosamine (Sia6LacNAc) is the product of b-galactoside a2,6-sialyltransferase (ST6Gal.1) (90, 91). Although a second enzyme able to mediate the a2,6-sialylation of lactosaminic chains, ST6Gal.2, was cloned (92, 93), its strict substrate specificity for oligosaccharides and its narrow tissue distribution leaves ST6Gal.1 as the major, if not the only enzyme responsible of the biosynthesis of Sia6LacNAc. This structure can be detected by the a2,6-sialyl-specific lectin from Sambucus nigra (SNA) (94) and, although widely expressed by normal tissues, shows a dramatic increase in several cancers (95, 96). We (97) and successively others (98-102) reported that ST6Gal.1 was increased in colon cancer tissues compared with normal mucosa. Other malignancies, including acute myeloid leukemia (103), choriocarcinoma (104), cervical carcinoma (105) gastric cancer (106) and some types of brain tumors (107) show an elevation of ST6Gal.1 activity or of the ST6Gal.1 transcript. As a consequence of the enhanced ST6Gal.1 expression, the vast majority of colon cancer specimens expresses an increased level of a2,6-sialylation of lactosaminic chains, as detected by SNA (108-110), although its level does not always correlate with that of ST6Gal.1 (110). A clinical study has indicated that high SNA reactivity is an independent predictive marker of poor prognosis (111). The CDw75 antigen is a peculiar form of a2,6-sialylated lactosamine, formerly identified in lymphocytes (112). This antigen is somehow different from that recognized by SNA in that colon cancer cells transfected with ST6Gal.1 exhibited SNA reactivity but not anti CDw75 reactivity (113). A recent study (98) has indicated that CDw75 is elevated in colorectal cancer, although its expression does not correlate with that of ST6Gal.1. In colon cancer, ST6Gal.1 over-expression leads also to the expression of an a1,2-fucosylated variant of Sia6LacNAc: the STH2 antigen (Fuca1-2(NeuAca2-6)Galb1-4GlcNAcb1-3Galb1-4Glc-Cer) (114). In human hepatocarcinomas, only a minority of the patients exhibits increased ST6Gal.1 expression (115), while ST6Gal.1 and a2,6-sialylated glycans show an altered distribution (116, 117). In breast cancer, high ST6Gal.1 is associated with poor prognosis markers, such as high grade and absence of progesterone receptor (118). Among brain tumors, ST6Gal.1 and Sia6LacNAc are expressed only by those of non-neuroectodermal origin (107). In general, among brain tumors, a more aggressive behavior appears to be related with reduced, rather than increased, expression of ST6Gal.1 and SNA reactivity (119).

Mice transgenic for the SV40 large T antigen under the control of a liver-specific promoter spontaneously develop well-differentiated hepatocellular carcinomas. In these animals, an elevated 2,6-sialylation of plasma and liver glycoproteins, as well as an increase of liver and serum ST6Gal.1 activity closely followed tumor progression (120). To reconcile these findings with the fact that only a minority of liver cancer cases displays increased ST6Gal.1 and a2,6-sialylation (115) we hypothesized that only a few of the multiple mechanisms of cell transformation operating in human hepatocarcinomas led to ST6Gal.1 activation.

Owing to the fact that ST6Gal.1 is transcriptionally regulated by the Ras pathway (discussed in section 5.1), it is not clear whether the obvious association of ST6Gal.1 activation with neoplastic transformation merely reflects the activation of the Ras pathway or is causally related to a growth advantage provided by Sia6LacNAc structures. This latter possibility was suggested by the observation that human colon cancer cell lines grown as nude mice xenografts, expressed increased levels of ST6Gal.1 and of Sia6LacNAc than cell lines grown in the usual in vitro conditions (121). To get insights into the causal role of ST6Gal.1 and of the cognate Sia6LacNAc structures in cancer progression, we (122) and others (123-125) stably inserted the ST6Gal.1 cDNA in different cell types. The analysis of these transfectants consistently indicated an increased adhesion of ST6Gal.1-expressing cells to extracellular matrix substrates, such as collagen, fibronectin and laminin in both colon cancer (124, 126) and breast cancer cell lines (123). Unexpectedly, in the colon cancer cell line SW948, ST6Gal.1 expression appeared to reduce the tumorigenic potential in nude mice and the ability to grow as a multilayer in vitro (126). Reduced invasive properties upon ST6Gal.1 transfection were described also in glioma cells (125, 127). Altogether, these data indicate that the relationship between expression of Sia6LacNAc termini and invasive growth is complex and probably strongly tissue dependent. An important clue on the role of a2,6-sialylation in tumor growth has been provided by a study showing that breast cancer tumors developed by PyMT mice (see section 3.1) displayed increased differentiation when developed in a ST6GAL1-null background (128). However, ST6Gal.1-null tumors displayed similar growth properties when compared with tumors developed by ST6Gal.1+/+ mice, indicating that at least in this mouse model of breast cancer, Sia6LacNAc termini play a role in tumor differentiation but not in tumor growth.

Several lines of evidence indicate that b1-integrins are crucial substrates of ST6Gal.1. a2,6-sialylation exerts opposite effect on of b1-integrin binding to extracellular substrates in colon cancer and in myeloid cells that is, it increases the adhesion (124, 126, 129, 130) and the expression of b1-integrins on the surface (126) of colon cancer cells while it decreases adhesion in myeloid cells (131, 132). A recent study (133) has provided the thermodynamic basis for the increased binding to fibronectin of desialylated b1-integrins. However, it is not clear how to reconcile these data with the observed increased binding of sialylated fibronectin in colon and breast cancer cells. A stronger binding of a2,6-sialylated b1-integrins to extracellular substrates can reinforce integrin-based signal transduction, as suggested by its increased binding to talin (124). In addition, a2,6-sialylation of b1-integrins can play a major role in cancer biology by reducing the binding of galectin-3 (134) a lectin which, in some circumstances, can exert a pro-apoptotic effect (135). Thus, the reduced binding of galectin-3 to ST6Gal.1-expressing cells would prevent their apoptotic death, resulting in increased malignancy. It is interesting to note that breast tumors developed by ST6GAL1-null mice (128) exhibited altered expression of genes associated with focal adhesion signaling and had decreased phosphorylation of focal adhesion kinase, a downstream target of b1-integrins.

It has been shown that exposure to ionizing radiations results in increased expression of ST6Gal.1 in both animals and cultured cell lines (136, 137). A causal relationship between high ST6Gal.1 expression and radiation resistance was indicated by the finding that transfection of ST6Gal.1 cDNA in colon cancer cell lines resulted in radiation resistance (137). Increased signaling through a2,6-sialylated b1-integrins is at the basis of this phenomenon (138), because of a stronger activation of paxillin and AKT signaling (139). It is known that the activation of these molecules leads to cell survival and to the activation of radiation-resistance pathways (140). These data depict a scenario in which increased expression of ST6Gal.1, by activation of the Ras pathway as discussed in section 5.1 or by other means leads to a2,6-sialylation of key membrane receptors, including b1 integrins, which convey activation and survival signal to cancer cells.

3.4. T, Tn and sialyl-Tn antigens

These low molecular weight sugar antigens derive from an incomplete synthesis of O-linked chains (25, 141, 142) (Figure 3). The Tn antigen is formed by a GalNAc linked to Serine or Threonine. This sugar can be substituted by a2,6-linked sialic acid, leading to the formation of sialyl-Tn antigen, or by a b1,3-linked galactose, forming the Thomsen-Friedenreich (T) antigen, or by a b1,3-linked GlcNAc, forming the core 3 structure. The b1,3-galactosyltransferase which mediates the formation of the T antigen (T-synthase) is peculiar because it requires the presence of a molecular chaperone, the product of the gene Cosmc (143) which, in the endoplasmic reticulum, binds to T synthase preventing its ubiquitin-mediated proteosomal degradation (144). While the presence of core-3 based glycans prevented colitis and colorectal cancer in a murine model (145), the expression of Tn, sTn and T antigens has often been correlated with cancer progression (146). During neoplastic transformation of breast epithelium, mucin glycosylation undergoes a characteristic switch from the expression of core 2 structures to accumulation of T (147-150) and sialyl-Tn structures (150, 151), (reviewed in (152)). In normal colonic tissues, T antigen is not expressed (153-155) because it is masked by sialylation (156). On the contrary, it is expressed by the majority of colon carcinoma specimens (153, 155) and by an even higher percentage of liver metastases (157). A molecular basis for the relationship between T-antigen expression and metastasis was provided by the observation that the interaction between this carbohydrate structure and galectin-3 could mediate both the homotypic aggregation of cancer cells (158, 159) and the docking of tumor cells to endothelial cells (160, 161). The homotypic aggregation protects cancer cells from the apoptosis induced by the lack of adhesion to extracellular substrates (anoikis) (159). The interactions between galectin-3 and the T antigen can be specifically inhibited by peptides (162, 163) which are able to inhibit both homo- and heterotypic cell adhesion and metastasis. In addition, the presence of cancer cells expressing the T antigen has been shown to induce the expression of galectin-3 by endothelial cells (164). Altogether, these data point to the interaction between galectin-3 and T antigen as an important determinant of cell malignancy (165). The exposure of the T antigen by colonic cells might be per se at the origin of proliferative signals. In fact, the binding to the T antigen of mitogenic dietary lectins (such as peanut lectin) results in increased cell proliferation (166) through stimulation of c-Met and MAPK (167); a similar stimulatory effect could be obtained by anti T antibodies (168). T antigen appears to be a possible target for cell-mediated anti cancer immunity. In fact, its expression increased NK susceptibility of cancer cells (169), while peptides containing the T antigen were able to elicit a specific and MHC class-I-restricted anti-tumor CTL response (170, 171). Moreover, anti-T antibodies were able to inhibit lung metastasis formation by breast cancer cells (172).

Despite the fact that breast cancer tissues often accumulate T antigen, ST3Gal.1 the enzyme which synthesizes sialyl T antigen, is usually elevated in breast cancer (173). The relationship between over-expression of ST3Gal.1 and breast cancer progression has recently been studied in a murine breast cancer model over-expressing ST3Gal.1 under the control of the MUC1 promoter (174). In ST3Gal.1 over-expressing mice, tumors developed with a shorter latency. However, this effect did not appear to be mediated by the accumulation of the sialyl-T antigen but, rather, by the mere over-expression of the sialyltransferase, suggesting the possibility that the enzyme acts as a tumor promoter (174). Interestingly, an elevation of ST3Gal.1 mRNA was reported also in bladder cancer specimens (175). The role of this modification in the biology of bladder cancer remains to be established.

Sialyl-Tn antigen is expressed by many malignancies, including stomach (176), liver (177), pancreas (178). In particular, in breast cancer its expression correlates with a poorly differentiated state (179) and resistance to adjuvant therapy in node-positive patients (180), while in colon cancer, sTn antigen is expressed by most primary tumors and metastasis and correlates with a worse prognosis (153, 157, 181, 182). The significance of sTn antigen as a tumor marker and its association with increased malignancy (183) suggested its use as a cancer vaccine (184, 185). Theratope is the commercial name given a conjugate formed by the sialyl-Tn disaccharide chemically linked to a highly immunogenic protein carrier. When administered to metastatic breast cancer patients, the conjugate induced an humoral as well as a cellular anti-cancer response. The protective effect of Theratope has been confirmed in a murine model of breast cancer (186).

The biological effects of sTn over-expression have been studied in cells over-expressing sialyltransferase ST6GalNAc.1, which is the major sTn synthase (187). In murine carcinoma cells, ST6GalNAc.1 over-expression led to sTn expression on b1-integrins, to major morphological changes and to reduced ability to migrate on fibronectin and hyaluronic acid (188). On the contrary, ST6GalNAc.1 over-expression in human breast cancer cell lines resulted in the expression of sTn antigen on MUC1 and other high molecular weight glycoproteins; this was associated with reduced cell adhesion and increased cell migration (189, 190).

T and sialyl Tn antigens are carried mainly by a high molecular weight splice variant of CD44 (191) and MUC1 (192-194) in colon cancer, by MUC2 in gastric cancer (176) and by MUC1 in breast cancer (194).

A general mechanism which has been proposed to be at the basis of the over-expression of Tn and sTn antigens in cancer is based on the somatic inactivation of the gene Cosmc which, in colon cancer and melanoma cell lines is associated with the expression of Tn and sTn antigens (143). These data confirm a previous observation (195) reporting that the down regulation of a carbohydrate structure can deviate the glycan biosynthesis towards alternative structures.

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3.5. Gangliosides

Gangliosides are sialic acid-containing glycolipids, whose expression is often deranged in cancer cells (4). In particular, accumulation of ganglioside GD3 is characteristic of melanoma (196-198), while accumulation of GD2 characterizes neuroblastoma (199). Gangliosides may play a role in cancer biology not only as cell surface structures (200), but also as molecules shed by the tumor, which can exert an immunosuppressive effect by sensitizing T lymphocytes to apoptosis (201). On the cell membrane, gangliosides are organized into complex structures known as glycosynapses, regions of the cell membrane where glycoconjugates are clustered with growth factor receptors and adhesion receptor (200, 202). The relevance of gangliosides as cancer-associated molecules has suggested their use as target for anti-cancer immunotherapy (203).

Key steps in ganglioside biosynthesis (Figure 5) are represented by the a2-3-sialylation of lactosylceramide, catalyzed by ST3Gal.5 (GM3 synthase), which results in GM3 synthesis, and by the a2-8 sialylation of GM3 by ST8Sia.1 (GD3 synthase), which yields GD3. GM3 and GD3 are the founders of the a- and b-series gangliosides respectively and are transformed in GM2 and GD2 respectively by the action of the same enzyme: b1,4GalNAcT-I (GM2/GD2 synthase). As a general rule, it appears that malignancy is positively associated with the expression of GD3 (25, 204-206) and negatively with that of GM3 (207-210). Expression of GD3 enhances in vivo growth and metastasis formation (211-215) through mechanisms involving interactions with both, receptors for growth factors such as c-Met (216) and receptors for the extracellular matrix, such as integrins (217). Interestingly, this interaction takes place between the carbohydrate portion of GD3 and the sugar chains of integrins (217). ST8Sia.1 transfection of a breast cancer cell line resulted in the activation of c-Met in the absence of its ligand, the hepatocyte growth factor (also known as scatter factor). This, in turns, resulted in the activation of both the PI3/AKT and MAPK signaling pathways (216). GD3 expression is necessary for VEGF signaling (215), and results in the activation of signaling molecules, such as focal adhesion kinase, paxillin and p130Cas (218, 219) and eventually of the Ras/MEK/ERK pathway (220). The over-expression of the tumor suppressor molecule caveolin-1 displaces GD3 from lipid rafts and inhibits paxillin and p130Cas activation, resulting in an attenuation of the malignant phenotype (221). The promoter region of GD3 synthase (ST8Sia.1) contains putative binding sites for transcription factors c-Ets-1, CREB, AP-1 and NF-kB (222), but appears to be regulated mainly by NF-kB (223).

The negative effect of GM3 on cell growth and malignancy is mediated through different mechanisms. It down-regulates EGF signaling (224) by interacting with its carbohydrate portions (225, 226). Moreover, GM3 inhibits VEGF (227), and PDGF (228) signaling, it associates with ErbB2 (229) and stimulates the expression of the cell cycle inhibitors p21(WAF1) and p27(kip1) through the tumor suppressor phosphatase PTEN (230). In addition, fibroblasts from ST3Gal.5-KO mice, lacking GM3 and a-series gangliosides, display a highly activated state of the MAPK pathway (231). However, these cells lack also GD3 and other b-series gangliosides; this indicates that the mere absence of GM3 in the absence of GD3 is sufficient to derange the MAPK pathway. GM3 induces apoptotic death in neuronal cells (232) and, in association with tetraspanin CD82, is able to inhibit c-Met signaling and its cross-talk with integrins, resulting in reduced cell motility (233, 234). In considering the relative contribution of GD3 and GM3 to the neoplastic phenotype, it should be kept in mind that a near complete ganglioside depletion in oncogene-transformed cells resulted in a dramatic inhibition of in vivo growth in syngeneic animals (235). Altogether, these results suggest that either the absence of GM3 or the over expression of GD3 are sufficient to exacerbate the neoplastic phenotype of cancer cells.

Beside the many studies indicating a role of GM3 in the attenuation of the neoplastic phenotype and of GD3 in its exacerbation, a few studies report that in given condition the opposite may happens (236-238). Very recently, it has been shown that over-expression of sialyltransferase ST6GalNAc.5 in glioma cells led to deranged expression of complex gangliosides, including increased expression of GM3 (239); these changes were associated with reduced malignancy.

4. MECHANISMS LEADING TO ALTERED GLYCAN STRUCTURES

Different mechanisms can account for the cancer-associated altered glycosylation pattern. These include the derangement of biosynthetic enzymes (e.g. glycosyltransferases, sugar nucleotide transporters) or of sugar degrading enzymes (e.g. glycosidases) and the masking of sugar epitopes by substituent groups. Examples of deranged glycosyltransferase expression have been provided in the preceding sections. In this chapter we will discuss other mechanisms.

4.1. Altered glycosidase expression

The best example of altered glycosidase activities in cancer is provided by Neu sialidases, a group of four enzymes (Neu1, lysosomal; Neu2, cytosolic; Neu3, cell membrane and Neu4, mitochondrial) showing marked alterations in cancer (240). Neu1, which is specific for oligosaccharides and glycopeptides, shows marked down-regulation in cancer, promoting anchorage-independent growth and metastatic ability. Over-expression of this enzyme in murine melanoma cells led to reversion of the malignant phenotype (241). Over-expression of cytosolic Neu2 also led to reduced invasion of cancer cells and to a concomitant reduction of sialylated molecules, such as GM3 and sLex (242). The ganglioside-specific, cell membrane-associated Neu3 displayed up-regulation in cancer. The mechanism through which Neu3 promotes cancer growth is related to inhibition of apoptosis through increased Bcl-2 and decreased caspase expression (243-245). The signal leading to apoptosis inhibition is originated at the plasma membrane and involves a potentiation of the EGFR signaling, resulting in the activation of the Ras cascade (243).

4.2. Masking of sugar structures by substituent groups

Cancer-associated sugar structures, such as sLex/sLea and sTn might be expressed also by normal tissues but their recognition by monoclonal antibodies can be hindered by substituent groups. In normal colon, the recognition of the sTn antigen is hindered by the O-acetylation of sialic acids. In fact, after de-acetylation of the samples by alkali treatment, the antigen appeared to be expressed at similar level by normal mucosa and colon cancer (246). However, this treatment rarely increased sTn expression in normal and neoplastic gastric and pancreatic tissues, suggesting that different mechanisms might be at the basis of the increased sTn expression in different tissues. O-acetylation of sialic acid plays a relevant role also in masking sLex in normal colonic tissues, in that after alkali treatment the expression of sLex carried by mucins in normal mucosa equaled that of cancer tissues (247). Our recent data (74, 76) confirms the expression of sLex in normal mucosa after de-acetylation of the samples. However, in cancer tissues the expression of sLex remained higher than in normal mucosa even after removal of O-acetyl groups (74).

Another example of the masking of a cancer-associated carbohydrate antigen is represented by the addition of a sulfate group linked to the 6 position of the GlcNAc residue of sLex in normal colonic mucosa, generating the sialyl 6-sulfo Lewisx antigen (Figure 4) (77). The presence of this antigen, which is highly expressed in non malignant colonic mucosa but poorly or not expressed by colon cancer (77), contributes to explain the low sLex expression in normal colon.

4.3. Altered expression of sugar and sugar nucleotide transporters

During the biosynthesis of the glycoconjugates, the addition of the more distal sugars (sialic acid, fucose, galactose) in the Golgi apparatus by the respective glycosyltransferases requires the availability of the appropriate sugar nucleotide donors inside the Golgi cisternae. These compounds are actively transported from the cytoplasmic side to the luminal side of the Golgi membranes by specific sugar nucleotide transporters. An involvement of a UDP-galactose transporter in the regulation of the expression of the cancer associated antigens T, sLea and sLex was indicated by a study showing that the mRNA of this transporter was up-regulated in colon cancer tissues, compared with normal mucosa (248). Transfection of this cDNA in SW1083 colon cancer cells resulted in elevation of T and sLea but not of sLex antigen, whereas transfection in SW480 cells resulted in little or no changes in the expression of T and sLea antigens but in strong elevation of sLex. This cell line-specific effect on sugar antigen biosynthesis of the UDP-galactose transporter suggests that it might be a limiting factor in the sugar antigen biosynthesis in some cell lines but not in others. Other examples of the influence of transporters on the biosynthesis of cancer-related sugar antigens are provided by the sialic acid transporter sialin (249) (discussed in section 5.2) and by the sulfate transporter DTDST (250), which is necessary for the biosynthesis of the sialyl 6-sulfo Lewisx antigen (section 4.2 and Figure 4). The down-regulation of this gene in colon cancer tissues (250) provides a molecular basis for the reduced expression of the sialyl 6-sulfo Lewisx antigen in colon cancer and for the concomitant over-expression of sLex (77).

4.4. Competition between normal and cancer-associated carbohydrate structures

The expression of a given carbohydrate antigen can be regulated by the level of expression of enzymes synthesizing alternative structures. In this chapter we will discuss some examples of this mechanism. A first example is provided by the competition between GnT5 and GnT3 in the biosynthesis of the N-linked chains (reviewed in (251)) (Figure 1). The addition of the bisecting GlcNAc inhibits the addition of the b1,6-branched chain (252, 253) and consequently, the elaboration of the polylactosaminic chains and of the terminal carbohydrate antigens (such as sLex). The main substrates of GnT3 are integrins (254), EGFR (255) and E-cadherin (256, 257). A negative effect of bisecting GlcNAc on cancer growth is suggested by several studies. For example, the addition of a bisecting GlcNAc on E-cadherin led to a down-regulation of tyrosine phosphorylation and to an altered localization of b-catenin after EGF stimulation (258), while the expression of GnT3 suppressed lung metastases of melanoma cells (259). Conversely, down-regulation of Wnt/b-catenin signaling led to reduced GnT3 expression and down-regulation of bisecting GlcNAc on b1-integrins (260). However, it has also been reported that under some circumstances bisecting GlcNAc can promote cancer growth. For example, in B16 melanoma cells expression of GnT3 led to the formation of bisecting structures on CD44 (261) which, in turns, led to increased adhesion to hyaluronate and increased tumor growth and metastasis. Moreover, circulating glycoproteins bearing bisecting GlcNAc promote hepatocyte proliferation (262). Nevertheless, the bulk of data supports the view that cell surface receptors modified by bisecting GlcNAc exert an inhibitory effect on cancer cell growth, in part by inhibition of the b1,6-branching.

Another example of competition between normal and cancer-associated structures is provided by the alternative presence of disialyl Lewisa or sLea antigens in normal and cancer colon, respectively (Figure 4) (263). The final steps of disialyl Lewisa biosynthesis, which is expressed mainly by normal mucosa and serves as ligand for the sialic acid binding inhibitory receptor Siglec-7 expressed by lymphoid cells (264), is mediated by the coordinate action of sialyltransferase ST6GalNAc.6 and fucosyltransferase 3 (Fuc-TIII) (265). Owing to the fact that sLea is not a substrate of ST6GalNAc.6, the biosynthesis of disialyl Lea can proceed only through the a2,6-sialylation of the GlcNAc residue of NeuAca2,3Galb1,3GlcNAc, followed by the Fuc-TIII-mediated addition of an a1,4-linked fucose (Figure 4). Thus, ST6GalNAc.6 and FucT-III contribute to the biosynthesis of this antigen in a manner that is at the same time cooperative and competitive. In fact, even though the contribution of both enzymes is necessary for the elaboration of this antigen, when the activity of ST6GalNAc.6 is not adequate (as occurs in colon cancer), only sLea antigen is synthesized.

Many of the studies on tissue expression of carbohydrate antigens utilized monoclonal antibodies. One of the few chemical analysis of the carbohydrate structure of mucins from normal and cancer colon reported the prevalence of a 3-sulfo Lewisx structure in which the a2,3 linked sialic acid of sLex was replaced by a sulfate group (266). In cancer mucin, this 3-sulfo Lex structure was down-regulated and sLex became predominant (266).

Another "normal" carbohydrate antigen whose down-regulation in cancer might be responsible for the expression of cancer-associated structures is the Sda antigen. This antigen is formed by a GalNAc b1,4-linked to the galactose residue of a2,3-sialylated lactosamine (Figure 4). The addition of this GalNAc residue is mediated by b4GalNAcT-II (also known as CT GalNAc transferase) (267), product of the B4GALNT2 gene. The enzyme is expressed at a very high level by normal colonic mucosa but is dramatically down-regulated in colon cancer (76, 268, 269). In vitro studies have shown that forced expression of this enzyme in colon and stomach cancer cell lines expressing the sLex or sLea antigens, resulted in the expression of the Sda antigen and in a dramatic down-regulation of sLea/sLex antigens (75, 76). This change was reported to be associated with a complete (stomach cells) or near complete (colon cells) loss of the metastatic potential (75). Moreover, structural studies have shown that the Sda or the sLex antigens can be expressed by colonic mucins in a mutually exclusive manner (270), in that the structures containing the b1,4-linked GalNAc on galactose did not contain the a1,3/4 fucose on GlcNAc. Altogether, these data strongly suggest that the cancer-associated down-regulation of b4GalNAcT-II plays a role in the expression of sLex/sLea antigens by cancer tissues.

Other glycosyltransferases have shown the potential to down-regulate sLex expression upon transfection in cancer cells. An example is provided by a1,2 fucosyltransferase I (Fuc-TI, product of FUT1 gene), whose expression has been reported to inhibit, through a competitive mechanism, the biosynthesis of sLex and the binding to E-selectin, without affecting the biosynthesis of sLea and P-selectin binding (271, 272). In HepG2 cells, this modification resulted in inhibition of vasculogenesis and tumor growth (63).

Another example is provided by the competition between ST3Gal.1, which synthesizes the sialyl-T antigen and core 2 GlcNAcT-1 (C2GnT1), which synthesizes core-2 branching (Figure 3) (273). The distribution of these enzymes along the Golgi apparatus displays a certain degree of overlapping, with C2GnT1 more proximal and ST3Gal.1 more distal. Transfection experiments have indicated that when ST3Gal.1 was increased, as occurs in breast cancer, the O-glycans of MUC1 became dominated by core 1 structures, even in the presence of C2GnT1 expression (273). Consistently, in the human colon cancer cell line SW480, C2GNT1 expression led to down-regulation of T antigen expression (274). In rat colon cancer cells, the expression of sTn appears to be controlled by the balance between the a2,6-sialyltransferase which synthesizes sTn and the GlcNAcTs which synthesize core 2 structures (275).

5. MECHANISMS OF REGULATION OF GLYCOGENES

Genes whose products are involved in the biosynthesis, degradation or recognition of carbohydrate chains can be referred to as "glycogenes". In this section we will discuss the mechanisms of regulation of these genes, with focus on glycosyltransferases and galectins.

5.1. Regulation of glycogenes by oncogenes and tumor suppressor genes

From the early papers published in the '80s, it turned out that transfected (276-278) or virally expressed (279, 280) oncogenes induced an increased size of the N-linked chains due mainly to increased b1,6 branching and increased expression of polylactosaminic chains. Among the oncogenes able to induce this effect were Ras (276-278), vfps/fes but not myc (278), while among viruses were polyoma (280) and Rous sarcoma viruses (279). The relationship between altered glycosylation and altered signal transduction is bidirectional. In fact, on the one hand the cancer-associated alterations of the signal transduction pathways frequently lead to increased expression of specific glycosyltransferases, resulting in altered glycosylation pattern (centrifugal relationship) (Figure 6). On the other hand, cancer-associated glycans expressed on cell membrane receptors can modify the cell signaling, resulting in the modulation of the basic properties of cancer cells (centripetal relationship, Figure 7). In the first case the alteration of the glycosylation pattern is the consequence of altered signaling, while in the second is the cause. Examples of the first relationship are mainly provided by MGAT5 and ST6GAL.1 genes, whose transcription is under the control of the ras/MAPK/Ets-1 pathway. MGAT5 is up-regulated by src (281), ErbB2 (282), v-sis (283) and Ras (284, 285) oncogenes, through Ets-1 (286, 287). Also sialyltransferase ST6Gal.1 is regulated by both N-ras and H-ras through RafGEF signaling (288-291). Other glycosyltransferases involved in increased branching of N-linked chains, such as galactosyltransferase-1 (292) and galactosyltransferase-5 (293) are under the control of Ets family members of transcription factors. Altogether, these data suggest that different upstream agents, signaling through the Ras pathway, cooperate in determining an increased size of N-linked chains.

In the pancreatic cancer cell line Capan1, expression of the tumor suppressor p16INK4a, which encodes an inhibitor of cyclin D CDK4/6 complex, restored the cell susceptibility to anoikis, and a profound alteration of the glycosylation machinery (294). p16INK4a induced increased expression of the fibronectin receptor integrin a5b1, altered expression of galactosyltransferase genes, down-regulation of a2,3-sialylation of O-linked chains and of a2,6-sialylation of N-linked chains. Decreased cell sialylation was accompanied by increased expression (and binding) of the pro-anoikis galectin-1, which interacts with the sugar chains of a5b1 integrin (295), while the expression of the anti-anoikis galectin-3 was decreased (296). Both, galectin-1 (297) and galectin-3 reinforce Ras-signaling (298) by directly interacting with Ras proteins. Through potentiation of the Ras signaling, cancer-derived galectin-1 facilitates cancer growth by stimulating the pro-angiogenic activity of endothelial cells (299). In addition, galectin-3 activity is regulated by c-abl-mediated phosphorylation of specific sites (300).

The metastasis-suppressor gene nm23-H1 has been reported to down regulate several glycosyltransferases involved in the biosynthesis of metastasis-associated structures, including GnT5 (301) as well as fucosyltransferases and sialyltransferases involved in sLex biosynthesis (302) and to inhibit integrin glycosylation resulting in reduced cell surface expression of b1 integrins (303). These effects are likely to play a role in the nm23-H1-induced reduction of the metastatic ability of cancer cells.

5.2. Glycosylation changes and hypoxia

Owing to the irregular and insufficient blood supply, large parts of a growing tumor can undergo hypoxia (insufficient oxygen supply). Cells respond to hypoxia through the hypoxia inducible factor (HIF), a dimeric transcription factor responsible for the transcription of several genes whose products compensate for the hypoxic conditions (304). The regulatory subunit of HIF is known as HIF-1a. The genes positively regulated by HIF-1a include those involved in angiogenesis, anaerobic metabolism, erythropoiesis and cell motility. In addition, recent findings have shown that also some glycosylation-related genes are under the control of HIF-1a (305). Colon cancer cell lines kept either in hypoxic conditions or in the presence of the hypoxia-mimic drug desferioxamine exhibited an increased expression of the selectin ligands sLex and sLea (306). The transcription of the mRNA of two glycosyltransferases potentially involved in selectin ligand biosynthesis, ST3Gal.1 and Fuc-TVII, was found to be under the control of HIF-1a and was increased in colon cancer tissues (306), suggesting that this increase is responsible for the augmented selectin ligand biosynthesis. However, the level of the FucT-VII transcript in colonic tissues is extremely low (72-74), consequently the contribution of this enzyme to sLex biosynthesis in colonic tissues is at least uncertain. Another gene stimulated by hypoxic conditions is that encoding for sialin, a sialic acid transporter (249). The over-expression of sialin resulted in increased expression of gangliosides containing the non-human sialic acid N-glycolyl-neuraminic acid (NeuGc). The presence of this non-human sugar in human cancer tissues and cell lines is due to the uptake from the diet or from bovine serum, respectively (307). These studies suggest that hypoxic conditions of tumor growth enhance incorporation of non-human sialic acid in gangliosides (308). Hypoxic conditions influence also the expression of sugar binding molecules such as galectin-1 (309). HIF-induced expression of galectin-1 in head and neck squamous cell carcinomas led to a reduced presence of tumor infiltrating lymphocytes, probably because of the known ability of galectin-1 to induce apoptosis of T lymphocytes (310). In colorectal cancer cell lines, HIF-dependent expression of galectin-1 is responsible for increased migration and invasion (311), indicating that this lectin is an important mediator of the effects of tumor hypoxia on cancer growth.

5.3. Epigenetic regulation

The best known examples of epigenetic regulation of gene expression include DNA methylation of CpG islands in gene promoter regions, chromatin alterations (i.e. histone acetylation, methylation, and ubiquitylation) and the expression of non-coding RNAs (312-314). The relevance of these modifications in cancer progression is increasingly recognized and the mutual interplay among these mechanisms is emerging as a novel paradigm of gene regulation (315). Many glycogenes appear to be aberrantly regulated in cancer because of epigenetic mechanisms (305, 316), including galectins (317-321), enzymes involved in the biosynthesis of sugar nucleotides (322, 323), transporters (250) and glycosyltransferases (264, 324-333). However, many of the cited studies were restricted to the investigation of the methylation status of the promoter region, usually through the use of the demethylating agent 5-aza-2-deoxycytidine (5-aza-dC). However, recent studies on hypermethylated tumor-suppressor promoters have reported only partial reactivation upon treatment, because they maintain several repressive histone modification marks (334, 335). Interestingly, a CpG island nearby the putative promoter region of the B4GALNT2 gene was found to be heavily methylated in colon cancer tissues (329), while treatment of colon cancer cell lines with 5-aza-dC resulted only in a partial recovery of enzyme expression (336). A similar behavior is displayed by the native promoter of b3GalT5, which lies in the context of two CpG islands (337). In fact, the activity of this promoter inversely correlated with the methylation status of the CpG islands in different cell lines, but 5-aza-dC treatment resulted in little or no effect on gene expression (Caretti, Dall'Olio, Trinchera, unpublished results). These data suggest that other glycogenes might be under the control of epigenetic mechanisms even if poorly responsive to 5-aza-dC. Consequently, the contribution of epigenetics to the regulation of glycosylation could be more relevant, as hypothesized (338).

6. PERSPECTIVE

The availability of genetically manipulated cell lines as well as of transgenic and knock-out mouse strains has allowed to establish unequivocally the causal role played by the cancer-associated glycosylation changes in cancer biology and to establish the multiple links between the cell glycosylation machinery and the signal transduction mechanisms. As depicted in Figure 6, the basic mechanisms controlling cell behavior affect the expression of cell surface carbohydrate structures and carbohydrate binding molecules, through "centrifugal" relationships. However, as depicted in Figure 7, carbohydrate structures on the cell membrane are able to affect the basic properties of cancer cells through "centripetal" relationships". These interactions appear to be integrated by a few types of molecules (including receptors of growth factors, integrins, galectin-3, E-cadherin), acting as "hubs". Glycosylation, like other post-translational modifications, has the potential to "fine tune" the interactions between cells and molecules. The full elucidation of these interactions, which are at the basis of the healthy development of complex organisms and are profoundly altered in cancer, is a major challenge of the post-genomic era and will provide the conceptual basis for therapeutic interventions aimed at the normalization of the cell surface of cancer cells.

7. ACKNOWLEDGEMENTS

Research was supported by grants from the University of Bologna and Pallotti Legacy for Cancer Research to F.D., from Mizutani Foundation for Glycosciences (2008) and the University of Insubria (FAR 2007-2008) to MT. We do apologize with the authors of the many important works that we have not been able to cite for space limitations.

8. REFERENCES

1. R. KornfeldS. Kornfeld: Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 54, 631-664 (1985).
doi:10.1146/annurev.bi.54.070185.003215
PMid:3896128

2. P. Van den Steen, P. M. Rudd, R. A. Dwek, G. Opdenakker: Concepts and principles of O-linked glycosylation. Crit Rev Biochem Mol Biol 33, 151-208 (1998).
doi:10.1080/10409239891204198
PMid:9673446

3. G. W. HartR. J. Copeland: Glycomics hits the big time. Cell 143, 672-676 (2010).

4. S. Hakomori: Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res 52, 257-331 (1989).
doi:10.1016/S0065-230X(08)60215-8
PMid:12149519    PMCid:124893

5. S. Hakomori: Glycosylation defining cancer malignancy: New wine in an old bottle. Proc Natl Acad Sci U S A 99, 10231-10233 (2002).
doi:10.1073/pnas.172380699
PMid:7679406    PMCid:287934

6. M. P. BevilacquaR. M. Nelson: Selectins. J Clin Invest 91, 379-387 (1993).
doi:10.1172/JCI116210
PMid:20452433

7. H. LaubliL. Borsig: Selectins promote tumor metastasis. Semin Cancer Biol 20, 169-177 (2010).
doi:10.1016/j.semcancer.2010.04.005
PMid:7542213

8. T. F. Tedder, D. A. Steeber, A. Chen, P. Engel: The selectins: vascular adhesion molecules. FASEB J 9, 866-873 (1995).
PMid:7542213

9. S. Califice, V. Castronovo, Brule F. Van den: Galectin-3 and cancer (Review). Int J Oncol 25, 983-992 (2004).
PMid:15375548

10. A. Danguy, I. Camby, R. Kiss: Galectins and cancer. Biochim Biophys Acta 1572, 285-293 (2002).
PMid:12223276

11. J. Dumic, S. Dabelic, M. Flogel: Galectin-3: An open-ended story. Biochim Biophys Acta 1760, 616-635 (2006).
PMid:16478649

12. O. B. GarnerL. G. Baum: Galectin-glycan lattices regulate cell-surface glycoprotein organization and signalling. Biochem Soc Trans 36, 1472-1477 (2008).
doi:10.1042/BST0361472
PMid:19021578    PMCid:2811491

13. F. T. LiuG. A. Rabinovich: Galectins as modulators of tumour progression. Nat Rev Cancer 5, 29-41 (2005).
doi:10.1038/nrc1527
PMid:15630413

14. N. L. Perillo, M. E. Marcus, L. G. Baum: Galectins: versatile modulators of cell adhesion, cell proliferation, and cell death. J Mol Med 76, 402-412 (1998).
doi:10.1007/s001090050232
PMid:9625297

15. F. Van den Brule, S. Califice, V. Castronovo: Expression of galectins in cancer: A critical review. Glycoconj J 19, 537-542 (2002).
doi:10.1023/B:GLYC.0000014083.48508.6a
PMid:14758077

16. J. W. Dennis, S. Laferte, C. Waghorne, M. L. Breitman, R. S. Kerbel: b 1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236, 582-585 (1987).
doi:10.1126/science.2953071
PMid:2953071

17. M. Granovsky, J. Fata, J. Pawling, W. J. Muller, R. Khokha, J. W. Dennis: Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med 6, 306-312 (2000).
doi:10.1038/73163
PMid:10700233

18. M. Demetriou, I. R. Nabi, M. Coppolino, S. Dedhar, J. W. Dennis: Reduced contact-inhibition and substratum adhesion in epithelial cells expressing GlcNAc-transferase V. J Cell Biol 130, 383-392 (1995).
doi:10.1083/jcb.130.2.383
PMid:7615638

19. K. S. LauJ. W. Dennis: N-Glycans in cancer progression. Glycobiology 18, 750-760 (2008).
doi:10.1093/glycob/cwn071
PMid:18701722

20. N. Taniguchi: A sugar-coated switch for cellular growth and arrest. Nat Chem Biol 3, 307-309 (2007).
doi:10.1038/nchembio0607-307
PMid:17510646

21. A. Lagana, J. G. Goetz, P. Cheung, A. Raz, J. W. Dennis, I. R. Nabi: Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in tumor cells. Mol Cell Biol 26, 3181-3193 (2006).
doi:10.1128/MCB.26.8.3181-3193.2006
PMid:16581792    PMCid:1446937

22. S. Ihara, E. Miyoshi, S. Nakahara, H. Sakiyama, H. Ihara, A. Akinaga, K. Honke, R. B. Dickson, C. Y. Lin, N. Taniguchi: Addition of b1-6 GlcNAc branching to the oligosaccharide attached to Asn 772 in the serine protease domain of matriptase plays a pivotal role in its stability and resistance against trypsin. Glycobiology 14, 139-146 (2004).
doi:10.1093/glycob/cwh013
PMid:14551220

23. S. Ihara, E. Miyoshi, J. H. Ko, K. Murata, S. Nakahara, K. Honke, R. B. Dickson, C. Y. Lin, N. Taniguchi: Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding b1-6 GlcNAc branching. J Biol Chem 277, 16960-16967 (2002).
doi:10.1074/jbc.M200673200
PMid:11864986

24. A. I. Markowska, F. T. Liu, N. Panjwani: Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J Exp Med 207, 1981-1993 (2010).
doi:10.1084/jem.20090121
PMid:20713592    PMCid:2931172

25. A. Cazet, S. Julien, M. Bobowski, M. A. Krzewinski-Recchi, A. Harduin-Lepers, S. Groux-Degroote, P. Delannoy: Consequences of the expression of sialylated antigens in breast cancer. Carbohydr Res 345, 1377-1383 (2010).
doi:10.1016/j.carres.2010.01.024
PMid:20231016

26. K. Shimodaira, J. Nakayama, N. Nakamura, O. Hasebe, T. Katsuyama, M. Fukuda: Carcinoma-associated expression of core 2 b1,6-N- acetylglucosaminyltransferase gene in human colorectal cancer: role of O-glycans in tumor progression. Cancer Res 57, 5201-5206 (1997).
PMid:9393734

27. J. L. Magnani, B. Nilsson, M. Brockhaus, D. Zopf, Z. Steplewski, H. Koprowski, V. Ginsburg: A monoclonal antibody-defined antigen associated with gastrointestinal cancer is a ganglioside containing sialylated lacto-N-fucopentaose II. J Biol Chem 257, 14365-14369 (1982).
PMid:7142214

28. D. Jordon, J. Jagirdar, M. Kaneko: Blood group antigens, Lewisx and Lewisy in the diagnostic discrimination of malignant mesothelioma versus adenocarcinoma. Am J Pathol 135, 931-937 (1989).
PMid:2817084    PMCid:1880090

29. H. S. Cooper, M. J. Malecha, C. Bass, P. L. Fagel, Z. Steplewski: Expression of blood group antigens H-2, Ley, and sialylated-Lea in human colorectal carcinoma. An immunohistochemical study using double-labeling techniques. Am J Pathol 138, 103-110 (1991).
PMid:1987759    PMCid:1886064

30. F. G. Hanisch, C. Hanski, A. Hasegawa: Sialyl Lewisx antigen as defined by monoclonal antibody AM-3 is a marker of dysplasia in the colonic adenoma-carcinoma sequence. Cancer Res 52, 3138-3144 (1992).
PMid:1350509

31. S. Sakamoto, T. Watanabe, T. Tokumaru, H. Takagi, H. Nakazato, K. O. Lloyd: Expression of Lewisa, Lewisb, Lewisx, Lewisy, siayl-Lewisa, and sialyl- Lewisx blood group antigens in human gastric carcinoma and in normal gastric tissue. Cancer Res 49, 745-752 (1989).
PMid:2910493

32. C. Cordon-Cardo, V. E. Reuter, C. L. Finstad, J. Sheinfeld, K. O. Lloyd, W. R. Fair, M. R. Melamed: Blood group-related antigens in human kidney: modulation of Lewis determinants in renal cell carcinoma. Cancer Res 49, 212-218 (1989).
PMid:2461798

33. C. Foxall, S. R. Watson, D. Dowbenko, C. Fennie, L. A. Lasky, M. Kiso, A. Hasegawa, D. Asa, B. K. Brandley: The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewisx oligosaccharide. J Cell Biol 117, 895-902 (1992).
doi:10.1083/jcb.117.4.895
PMid:1374413

34. G. Mannori, P. Crottet, O. Cecconi, K. Hanasaki, A. Aruffo, R. M. Nelson, A. Varki, M. P. Bevilacqua: Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Res 55, 4425-4431 (1995).
PMid:7545541

35. M. L. Phillips, E. Nudelman, F. C. Gaeta, M. Perez, A. K. Singhal, S. Hakomori, J. C. Paulson: ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. Science 250, 1130-1132 (1990).

36. J. D. MarthP. K. Grewal: Mammalian glycosylation in immunity. Nat Rev Immunol 8, 874-887 (2008).
doi:10.1038/nri2417
PMid:18846099    PMCid:2768770

37. K. A. Paschos, D. Canovas, N. C. Bird: The engagement of selectins and their ligands in colorectal cancer liver metastases. J Cell Mol Med 14, 165-174 (2010).
doi:10.1111/j.1582-4934.2009.00852.x
PMid:19627399

38. I. P. Witz: The selectin-selectin ligand axis in tumor progression. Cancer Metastasis Rev 27, 19-30 (2008).
doi:10.1007/s10555-007-9101-z
PMid:18180878

39. R. Renkonen, P. Mattila, M. L. Majuri, J. Rabina, S. Toppila, J. Renkonen, L. Hirvas, J. Niittymaki, J. P. Turunen, O. Renkonen, T. Paavonen: In vitro experimental studies of sialyl Lewis x and sialyl Lewis a on endothelial and carcinoma cells: crucial glycans on selectin ligands. Glycoconj J 14, 593-600 (1997).
doi:10.1023/A:1018536509950
PMid:9298692

40. W. D. Hanley, M. M. Burdick, K. Konstantopoulos, R. Sackstein: CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity. Cancer Res 65, 5812-5817 (2005).
doi:10.1158/0008-5472.CAN-04-4557
PMid:15994957

41. K. T. Lim, K. Miyazaki, N. Kimura, M. Izawa, R. Kannagi: Clinical application of functional glycoproteomics - dissection of glycotopes carried by soluble CD44 variants in sera of patients with cancers. Proteomics 8, 3263-3273 (2008).
doi:10.1002/pmic.200800147
PMid:18690645

42. C. Hanski, K. Drechsler, F. G. Hanisch, J. Sheehan, M. Manske, D. Ogorek, E. Klussmann, M. L. Hanski, M. Blank, P. X. Xing, .: Altered glycosylation of the MUC-1 protein core contributes to the colon carcinoma-associated increase of mucin-bound sialyl-Lewisx expression. Cancer Res 53, 4082-4088 (1993).
PMid:7689422

43. J. J. Ho, B. Siddiki, Y. S. Kim: Association of sialyl-Lewisa and sialyl-Lewisx with MUC-1 apomucin in a pancreatic cancer cell line. Cancer Res 55, 3659-3663 (1995).
PMid:7627976

44. J. Tomlinson, J. L. Wang, S. H. Barsky, M. C. Lee, J. Bischoff, M. Nguyen: Human colon cancer cells express multiple glycoprotein ligands for E- selectin. Int J Oncol 16, 347-353 (2000).
PMid:10639580

45. R. Kannagi: Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J 14, 577-584 (1997).
doi:10.1023/A:1018532409041
PMid:9298690

46. D. Ichikawa, K. Kitamura, N. Tani, S. Nishida, H. Tsurutome, S. I. Hakomori, E. Ikeda, F. Mutoh, H. Kurioka, H. Yamagishi: Molecular detection of disseminated cancer cells in the peripheral blood and expression of sialylated antigens in colon cancers. J Surg Oncol 75, 98-102 (2000).
doi:10.1002/1096-9098(200010)75:2<98::AID-JSO5>3.0.CO;2-R

47. S. Nakamori, M. Kameyama, S. Imaoka, H. Furukawa, O. Ishikawa, Y. Sasaki, T. Kabuto, T. Iwanaga, Y. Matsushita, T. Irimura: Increased expression of sialyl Lewisx antigen correlates with poor survival in patients with colorectal carcinoma: clinicopathological and immunohistochemical study. Cancer Res 53, 3632-3637 (1993).
PMid:8101764

48. S. Nakamori, M. Kameyama, S. Imaoka, H. Furukawa, O. Ishikawa, Y. Sasaki, Y. Izumi, T. Irimura: Involvement of carbohydrate antigen sialyl Lewisx in colorectal cancer metastasis. Dis Colon Rectum 40, 420-431 (1997).
doi:10.1007/BF02258386

49. N. Yamada, Y. S. Chung, K. Maeda, T. Sawada, T. Ikehara, H. Nishino, M. Okuno, M. Sowa: Increased expression of sialyl Lewis A and sialyl Lewis X in liver metastases of human colorectal carcinoma. Invasion Metastasis 15, 95-102 (1995).
PMid:8621274

50. K. Tozawa, T. Okamoto, N. Kawai, Y. Hashimoto, Y. Hayashi, K. Kohri: Positive correlation between sialyl Lewis X expression and pathologic findings in renal cell carcinoma. Kidney Int 67, 1391-1396 (2005).
doi:10.1111/j.1523-1755.2005.00216.x
PMid:15780091

51. J. Wei, L. Cui, F. Liu, Y. Fan, R. Lang, F. Gu, X. Guo, P. Tang, L. Fu: E-selectin and Sialyl Lewis X expression is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast. Int J Surg Pathol 18, 193-200 (2010).
doi:10.1177/1066896908320832
PMid:18611928

52. N. Matsuura, T. Narita, C. Mitsuoka, N. Kimura, R. Kannagi, T. Imai, H. Funahashi, H. Takagi: Increased level of circulating adhesion molecules in the sera of breast cancer patients with distant metastases. Jpn J Clin Oncol 27, 135-139 (1997).
doi:10.1093/jjco/27.3.135
PMid:9255266

53. P. Sozzani, R. Arisio, M. Porpiglia, C. Benedetto: Is Sialyl Lewis x antigen expression a prognostic factor in patients with breast cancer? Int J Surg Pathol 16, 365-374 (2008).
doi:10.1177/1066896908324668
PMid:18977761

54. K. M. Hiller, J. P. Mayben, K. M. Bendt, G. A. Manousos, K. Senger, H. S. Cameron, B. W. Weston: Transfection of a1,3 fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells. Mol Carcinog 27, 280-288 (2000).
doi:10.1002/(SICI)1098-2744(200004)27:4<280::AID-MC6>3.0.CO;2-L

55. A. Opolski, A. Laskowska, J. Madej, J. Wietrzyk, A. Klopocki, C. Radzikowski, M. Ugorski: Metastatic potential of human CX-1 colon adenocarcinoma cells is dependent on the expression of sialosyl Lea antigen. Clin Exp Metastasis 16, 673-681 (1998).
doi:10.1023/A:1006502009682

56. B. W. Weston, K. M. Hiller, J. P. Mayben, G. A. Manousos, K. M. Bendt, R. Liu, J. C. Cusack, Jr.: Expression of human a1,3 fucosyltransferase antisense sequences inhibits selectin-mediated adhesion and liver metastasis of colon carcinoma cells. Cancer Res 59, 2127-2135 (1999).
PMid:10232599

57. X. Yin, K. Rana, V. Ponmudi, M. R. King: Knockdown of fucosyltransferase III disrupts the adhesion of circulating cancer cells to E-selectin without affecting hematopoietic cell adhesion. Carbohydr Res 345, 2334-2342 (2010).
doi:10.1016/j.carres.2010.07.028
PMid:20833389

58. M. Perez-Garay, B. Arteta, L. Pages, R. De Llorens, C. de Bolos, F. Vidal-Vanaclocha, R. Peracaula: a2,3-sialyltransferase ST3Gal III modulates pancreatic cancer cell motility and adhesion in vitro and enhances its metastatic potential in vivo. PLoS One 5 (2010).

59. O. Saitoh, W. C. Wang, R. Lotan, M. Fukuda: Differential glycosylation and cell surface expression of lysosomal membrane glycoproteins in sublines of a human colon cancer exhibiting distinct metastatic potentials. J Biol Chem 267, 5700-5711 (1992).
PMid:1544942

60. N. Yamada, Y. S. Chung, S. Takatsuka, Y. Arimoto, T. Sawada, T. Dohi, M. Sowa: Increased sialyl Lewis A expression and fucosyltransferase activity with acquisition of a high metastatic capacity in a colon cancer cell line. Br J Cancer 76, 582-587 (1997).
doi:10.1038/bjc.1997.429
PMid:9303355    PMCid:2228023

61. M. ThurinT. Kieber-Emmons: SA-Lea and Tumor Metastasis: The Old Prediction and Recent Findings. Hybrid Hybridomics 21, 111-116 (2002).
doi:10.1089/153685902317401708
PMid:12031100

62. K. Tei, N. Kawakami-Kimura, O. Taguchi, K. Kumamoto, S. Higashiyama, N. Taniguchi, K. Toda, R. Kawata, Y. Hisa, R. Kannagi: Roles of cell adhesion molecules in tumor angiogenesis induced by cotransplantation of cancer and endothelial cells to nude rats. Cancer Res 62, 6289-6296 (2002).
PMid:12414659

63. S. Mathieu, R. Gerolami, J. Luis, S. Carmona, O. Kol, L. Crescence, S. Garcia, P. Borentain, A. El Battari: Introducing a1,2-linked fucose into hepatocarcinoma cells inhibits vasculogenesis and tumor growth. Int J Cancer 121, 1680-1689 (2007).
doi:10.1002/ijc.22797
PMid:17583578

64. C. Ohyama, S. Tsuboi, M. Fukuda: Dual roles of sialyl Lewis X oligosaccharides in tumor metastasis and rejection by natural killer cells. EMBO J 18, 1516-1525 (1999).
doi:10.1093/emboj/18.6.1516
PMid:10075923    PMCid:1171240

65. C. Ohyama, S. Kanto, K. Kato, O. Nakano, Y. Arai, T. Kato, S. Chen, M. N. Fukuda, M. Fukuda: Natural killer cells attack tumor cells expressing high levels of sialyl Lewis x oligosaccharides. Proc Natl Acad Sci U S A 99, 13789-13794 (2002).
doi:10.1073/pnas.212456599
PMid:12370411    PMCid:129776

66. A. S. Carvalho, A. Harduin-Lepers, A. Magalhaes, E. Machado, N. Mendes, L. T. Costa, R. Matthiesen, R. Almeida, J. Costa, C. A. Reis: Differential expression of a-2,3-sialyltransferases and a-1,3/4-fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. Int J Biochem Cell Biol 42, 80-89 (2010).
doi:10.1016/j.biocel.2009.09.010

67. P. V. Beum, J. Singh, M. Burdick, M. A. Hollingsworth, P. W. Cheng: Expression of core 2 b1,6-N-acetylglucosaminyltransferase in a human pancreatic cancer cell line results in altered expression of MUC1 tumor-associated epitopes. J Biol Chem 274, 24641-24648 (1999).
doi:10.1074/jbc.274.35.24641
PMid:10455130

68. N. Matsuura, T. Narita, N. Hiraiwa, M. Hiraiwa, H. Murai, T. Iwase, H. Funahashi, T. Imai, H. Takagi, R. Kannagi: Gene expression of fucosyl- and sialyl-transferases which synthesize sialyl Lewisx, the carbohydrate ligands for E-selectin, in human breast cancer. Int J Oncol 12, 1157-1164 (1998).
PMid:9538143

69. A. Togayachi, T. Kudo, Y. Ikehara, H. Iwasaki, S. Nishihara, T. Andoh, M. Higashiyama, K. Kodama, S. Nakamori, H. Narimatsu: Up-regulation of Lewis enzyme (Fuc-TIII) and plasma-type a1,3fucosyltransferase (Fuc-TVI) expression determines the augmented expression of sialyl Lewis x antigen in non-small cell lung cancer. Int J Cancer 83, 70-79 (1999).
doi:10.1002/(SICI)1097-0215(19990924)83:1<70::AID-IJC14>3.0.CO;2-K

70. S. Nakamori, S. Nishihara, Y. Ikehara, H. Nagano, K. Dono, M. Sakon, H. Narimatsu, M. Monden: Molecular mechanism involved in increased expression of sialyl Lewis antigens in ductal carcinoma of the pancreas. J Exp Clin Cancer Res 18, 425-432 (1999).
PMid:10606190

71. T. Dohi, M. Hashiguchi, S. Yamamoto, H. Morita, M. Oshima: Fucosyltransferase-producing sialyl Lea and sialyl Lex carbohydrate antigen in benign and malignant gastrointestinal mucosa. Cancer 73, 1552-1561 (1994).
doi:10.1002/1097-0142(19940315)73:6<1552::AID-CNCR2820730605>3.0.CO;2-6

72. H. Ito, N. Hiraiwa, M. Sawada-Kasugai, S. Akamatsu, T. Tachikawa, Y. Kasai, S. Akiyama, K. Ito, H. Takagi, R. Kannagi: Altered mRNA expression of specific molecular species of fucosyl- and sialyl-transferases in human colorectal cancer tissues. Int J Cancer 71, 556-564 (1997).
doi:10.1002/(SICI)1097-0215(19970516)71:4<556::AID-IJC9>3.0.CO;2-T

73. T. Kudo, Y. Ikehara, A. Togayachi, K. Morozumi, M. Watanabe, M. Nakamura, S. Nishihara, H. Narimatsu: Up-regulation of a set of glycosyltransferase genes in human colorectal cancer. Lab Invest 78, 797-811 (1998).
PMid:9690558

74. M. Trinchera, N. Malagolini, M. Chiricolo, D. Santini, F. Minni, A. Caretti, F. Dall'Olio: The biosynthesis of the selectin-ligand sialyl Lewis x in colorectal cancer tissues is regulated by fucosyltransferase VI and can be inhibited by an RNA interference-based approach. Int J Biochem Cell Biol 43, 130-139 (2011).
doi:10.1016/j.biocel.2010.10.004

75. Y. I. Kawamura, R. Kawashima, R. Fukunaga, K. Hirai, N. Toyama-Sorimachi, M. Tokuhara, T. Shimizu, T. Dohi: Introduction of Sda carbohydrate antigen in gastrointestinal cancer cells eliminates selectin ligands and inhibits metastasis. Cancer Res 65, 6220-6227 (2005).
doi:10.1158/0008-5472.CAN-05-0639
PMid:16024623

76. N. Malagolini, D. Santini, M. Chiricolo, F. Dall'Olio: Biosynthesis and expression of the Sda and sialyl Lewis x antigens in normal and cancer colon. Glycobiology 17, 688-697 (2007).
doi:10.1093/glycob/cwm040
PMid:17395692

77. M. Izawa, K. Kumamoto, C. Mitsuoka, C. Kanamori, A. Kanamori, K. Ohmori, H. Ishida, S. Nakamura, K. Kurata-Miura, K. Sasaki, T. Nishi, R. Kannagi: Expression of sialyl 6-sulfo Lewis X is inversely correlated with conventional sialyl Lewis X expression in human colorectal cancer. Cancer Res 60, 1410-1416 (2000).
PMid:10728707

78. E. H. Holmes, S. Hakomori, G. K. Ostrander: Synthesis of type 1 and 2 lacto series glycolipid antigens in human colonic adenocarcinoma and derived cell lines is due to activation of a normally unexpressed b1,3N-acetylglucosaminyltransferase. J Biol Chem 262, 15649-15658 (1987).
PMid:2960671

79. N. T. Marcos, A. Magalhaes, B. Ferreira, M. J. Oliveira, A. S. Carvalho, N. Mendes, T. Gilmartin, S. R. Head, C. Figueiredo, L. David, F. Santos-Silva, C. A. Reis: Helicobacter pylori induces b3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl-Lewis x. J Clin Invest 118, 2325-2336 (2008).
PMid:18483624    PMCid:2381748

80. E. H. Holmes, G. K. Ostrander, H. Clausen, N. Graem: Oncofetal expression of Lex carbohydrate antigens in human colonic adenocarcinomas. Regulation through type 2 core chain synthesis rather than fucosylation. J Biol Chem 262, 11331-11338 (1987).
PMid:3112156

81. T. Ichikawa, J. Nakayama, N. Sakura, T. Hashimoto, M. Fukuda, M. N. Fukuda, T. Taki: Expression of N-acetyllactosamine and b1,4-galactosyltransferase (b4GalT-I) during adenoma-carcinoma sequence in the human colorectum. J Histochem Cytochem 47, 1593-1602 (1999).
PMid:10567443

82. W. S. Chen, H. Y. Chang, C. P. Li, J. M. Liu, T. S. Huang: Tumor b-1,4-galactosyltransferase IV overexpression is closely associated with colorectal cancer metastasis and poor prognosis. Clin Cancer Res 11, 8615-8622 (2005).
doi:10.1158/1078-0432.CCR-05-1006
PMid:16361545

83. A. Bardoni, M. Valli, M. Trinchera: Differential expression of b1,3galactosyltransferases in human colon cells derived from adenocarcinomas or normal mucosa. FEBS Lett 451, 75-80 (1999).
doi:10.1016/S0014-5793(99)00547-5

84. S. Isshiki, A. Togayachi, T. Kudo, S. Nishihara, M. Watanabe, T. Kubota, M. Kitajima, N. Shiraishi, K. Sasaki, T. Andoh, H. Narimatsu: Cloning, expression, and characterization of a novel UDP-galactose:b- N-acetylglucosamine b1,3-galactosyltransferase (b3Gal-T5) responsible for synthesis of type 1 chain in colorectal and pancreatic epithelia and tumor cells derived therefrom. J Biol Chem 274, 12499-12507 (1999).
doi:10.1074/jbc.274.18.12499
PMid:10212226

85. S. Isshiki, T. Kudo, S. Nishihara, Y. Ikehara, A. Togayachi, A. Furuya, K. Shitara, T. Kubota, M. Watanabe, M. Kitajima, H. Narimatsu: Lewis type 1 antigen synthase (b3Gal-T5) is transcriptionally regulated by homeoproteins. J Biol Chem 278, 36611-36620 (2003).
doi:10.1074/jbc.M302681200
PMid:12855703

86. R. Salvini, A. Bardoni, M. Valli, M. Trinchera: b1,3-Galactosyltransferase b3Gal-T5 acts on the GlcNAcb1-- >3Galb1-->4GlcNAcb1-->R sugar chains of carcinoembryonic antigen and other N-linked glycoproteins and is down-regulated in colon adenocarcinomas. J Biol Chem 276, 3564-3573 (2001).
doi:10.1074/jbc.M006662200
PMid:11058588

87. A. Seko, T. Ohkura, H. Kitamura, S. Yonezawa, E. Sato, K. Yamashita: Quantitative differences in GlcNAc:b1-->3 and GlcNAc:b1-->4 galactosyltransferase activities between human colonic adenocarcinomas and normal colonic mucosa. Cancer Res 56, 3468-3473 (1996).
PMid:8758913

88. L. MareM. Trinchera: Suppression of b1,3galactosyltransferase b3Gal-T5 in cancer cells reduces sialyl-Lewis a and enhances poly N-acetyllactosamines and sialyl-Lewis x on O-glycans. Eur J Biochem 271, 186-194 (2004).
doi:10.1046/j.1432-1033.2003.03919.x

89. N. Uozumi, C. Gao, T. Yoshioka, M. Nakano, K. Moriwaki, T. Nakagawa, T. Masuda, M. Tanabe, E. Miyoshi: Identification of a novel type of CA19-9 carrier in human bile and sera of cancer patients: an implication of the involvement in nonsecretory exocytosis. J Proteome Res 9, 6345-6353 (2010).
doi:10.1021/pr100600u
PMid:20954701

90. J. Weinstein, U. de Souza e Silva, J. C. Paulson: Purification of a Gal b 1,4GlcNAc a 2,6 sialyltransferase and a Gal b 1,3(4)GlcNAc a 2,3 sialyltransferase to homogeneity from rat liver. J Biol Chem 257, 13835-13844 (1982).
PMid:7142179

91. J. Weinstein, E. U. Lee, K. McEntee, P. H. Lai, J. C. Paulson: Primary structure of b-galactoside a 2,6-sialyltransferase. Conversion of membrane-bound enzyme to soluble forms by cleavage of the NH2-terminal signal anchor. J Biol Chem 262, 17735-17743 (1987).
PMid:3121604

92. M. A. Krzewinski-Recchi, S. Julien, S. Juliant, M. Teintenier-Lelievre, B. Samyn-Petit, M. D. Montiel, A. M. Mir, M. Cerutti, A. Harduin-Lepers, P. Delannoy: Identification and functional expression of a second human b-galactoside a2,6-sialyltransferase, ST6Gal II. Eur J Biochem 270, 950-961 (2003).
doi:10.1046/j.1432-1033.2003.03458.x
PMid:12603328

93. S. Takashima, S. Tsuji, M. Tsujimoto: Characterization of the Second Type of Human b-Galactoside a2,6-Sialyltransferase (ST6Gal II), Which Sialylates Galb1,4GlcNAc Structures on Oligosaccharides Preferentially. Genomic Analysis of Human Sialyltransferase Genes. J Biol Chem 277, 45719-45728 (2002).
doi:10.1074/jbc.M206808200
PMid:12235148

94. N. Shibuya, I. J. Goldstein, W. F. Broekaert, M. Nsimba-Lubaki, B. Peeters, W. J. Peumans: The elderberry (Sambucus nigra L.) bark lectin recognizes the Neu5Ac(a 2-6)Gal/GalNAc sequence. J Biol Chem 262, 1596-1601 (1987).
PMid:3805045

95. F. Dall'Olio: The sialyl-a2,6-lactosaminyl-structure: biosynthesis and functional role. Glycoconj J 17, 669-676 (2000).
doi:10.1023/A:1011077000164
PMid:11425186

96. F. Dall'OlioM. Chiricolo: Sialyltransferases in cancer. Glycoconj J 18, 841-850 (2001).
doi:10.1023/A:1022288022969
PMid:12820717

97. F. Dall'Olio, N. Malagolini, G. Di Stefano, F. Minni, D. Marrano, F. Serafini-Cessi: Increased CMP-NeuAc:Galb1,4GlcNAc-R a 2,6 sialyltransferase activity in human colorectal cancer tissues. Int J Cancer 44, 434-439 (1989).
doi:10.1002/ijc.2910440309

98. C. Costa-Nogueira, S. Villar-Portela, E. Cuevas, E. Gil-Martin, A. Fernandez-Briera: Synthesis and expression of CDw75 antigen in human colorectal cancer. BMC Cancer 9, 431 (2009).
doi:10.1186/1471-2407-9-431
PMid:20003255    PMCid:2803195

99. P. Gessner, S. Riedl, A. Quentmaier, W. Kemmner: Enhanced activity of CMP-NeuAc:Gal b 1-4GlcNAc:a 2,6-sialyltransferase in metastasizing human colorectal tumor tissue and serum of tumor patients. Cancer Lett 75, 143-149 (1993).
doi:10.1016/0304-3835(93)90056-F

100. W. Kemmner, D. Kruck, P. Schlag: Different sialyltransferase activities in human colorectal carcinoma cells from surgical specimens detected by specific glycoprotein and glycolipid acceptors. Clin Exp Metastasis 12, 245-254 (1994).
doi:10.1007/BF01753893

101. A. Gangopadhyay, S. P. Perera, P. Thomas: Differential expression of a2,6-sialyltransferase in colon tumors recognized by a monoclonal antibody. Hybridoma 17, 117-123 (1998).
doi:10.1089/hyb.1998.17.117
PMid:9627051

102. T. Petretti, W. Kemmner, B. Schulze, P. M. Schlag: Altered mRNA expression of glycosyltransferases in human colorectal carcinomas and liver metastases. Gut 46, 359-366 (2000).
PMid:1679356

103. P. O. Skacel, A. J. Edwards, C. T. Harrison, W. M. Watkins: Enzymic control of the expression of the X determinant (CD15) in human myeloid cells during maturation: the regulatory role of 6- sialytransferase. Blood 78, 1452-1460 (1991).
PMid:9766657

104. K. Fukushima, S. Hara-Kuge, A. Seko, Y. Ikehara, K. Yamashita: Elevation of a2,6 sialyltransferase and a1,2 fucosyltransferase activities in human choriocarcinoma. Cancer Res 58, 4301-4306 (1998).
PMid:11585423

105. P. H. Wang, Y. F. Li, C. M. Juang, Y. R. Lee, H. T. Chao, Y. C. Tsai, C. C. Yuan: Altered mRNA expression of sialyltransferase in squamous cell carcinomas of the cervix. Gynecol Oncol 83, 121-127 (2001).
doi:10.1006/gyno.2001.6358
PMid:8834541

106. L. Jun, W. Yuanshu, X. Yanying, X. Zhongfa, Y. Jian, W. Fengling, Q. Xianjun, N. Kokudo, T. Wei, Z. Weixia, C. Shuxiang: Altered mRNA expressions of sialyltransferases in human gastric cancer tissues. Med Oncol (2010).

107. Y. Kaneko, H. Yamamoto, D. S. Kersey, K. J. Colley, J. E. Leestma, J. R. Moskal: The expression of Gal b 1,4GlcNAc a 2,6 sialyltransferase and a 2,6-linked sialoglycoconjugates in human brain tumors. Acta Neuropathol (Berl) 91, 284-292 (1996).
doi:10.1007/s004010050427
PMid:7693064

108. F. Dall'OlioD. Trere: Expression of a 2,6-sialylated sugar chains in normal and neoplastic colon tissues. Detection by digoxigenin-conjugated Sambucus nigra agglutinin. Eur J Histochem 37, 257-265 (1993).
PMid:1661075    PMCid:1886452

109. T. Sata, J. Roth, C. Zuber, B. Stamm, P. U. Heitz: Expression of a2,6-linked sialic acid residues in neoplastic but not in normal human colonic mucosa. A lectin-gold cytochemical study with Sambucus nigra and Maackia amurensis lectins. Am J Pathol 139, 1435-1448 (1991).

110. F. Dall'Olio, M. Chiricolo, C. Ceccarelli, F. Minni, D. Marrano, D. Santini: b-galactoside a2,6 sialyltransferase in human colon cancer: contribution of multiple transcripts to regulation of enzyme activity and reactivity with Sambucus nigra agglutinin. Int J Cancer 88, 58-65 (2000).
doi:10.1002/1097-0215(20001001)88:1<58::AID-IJC9>3.0.CO;2-Q

111. M. J. Vierbuchen, W. Fruechtnicht, S. Brackrock, K. T. Krause, T. J. Zienkiewicz: Quantitative lectin-histochemical and immunohistochemical studies on the occurrence of a(2,3)- and a(2,6)-linked sialic acid residues in colorectal carcinomas. Relation to clinicopathologic features. Cancer 76, 727-735 (1995).
doi:10.1002/1097-0142(19950901)76:5<727::AID-CNCR2820760504>3.0.CO;2-R
PMid:1730763

112. B. J. Bast, L. J. Zhou, G. J. Freeman, K. J. Colley, T. J. Ernst, J. M. Munro, T. F. Tedder: The HB-6, CDw75, and CD76 differentiation antigens are unique cell- surface carbohydrate determinants generated by the b-galactoside a 2,6-sialyltransferase. J Cell Biol 116, 423-435 (1992).
doi:10.1083/jcb.116.2.423
PMid:11722575

113. F. Dall'Olio, M. Chiricolo, E. Mariani, A. Facchini: Biosynthesis of the cancer-related sialyl-a2,6-lactosaminyl epitope in colon cancer cell lines expressing b-galactoside a2,6- sialyltransferase under a constitutive promoter. Eur J Biochem 268, 5876-5884 (2001).
doi:10.1046/j.0014-2956.2001.02536.x
PMid:20656882

114. H. Korekane, A. Matsumoto, F. Ota, T. Hasegawa, Y. Misonou, K. Shida, Y. Miyamoto, N. Taniguchi: Involvement of ST6Gal I in the biosynthesis of a unique human colon cancer biomarker candidate, a2,6-sialylated blood group type 2H (ST2H) antigen. J Biochem 148, 359-370 (2010).
doi:10.1093/jb/mvq077
PMid:14514712

115. F. Dall'Olio, M. Chiricolo, A. D'Errico, E. Gruppioni, A. Altimari, M. Fiorentino, W. F. Grigioni: Expression of b-galactoside a2,6 sialyltransferase and of a2,6-sialylated glycoconjugates in normal human liver, hepatocarcinoma, and cirrhosis. Glycobiology 14, 39-49 (2004).
doi:10.1093/glycob/cwh002
PMid:12429811

116. Y. Cao, A. Merling, P. R. Crocker, R. Keller, R. Schwartz-Albiez: Differential expression of b-galactoside a2,6 sialyltransferase and sialoglycans in normal and cirrhotic liver and hepatocellular carcinoma. Lab Invest 82, 1515-1524 (2002).
PMid:9751611

117. J. Souady, M. Hulsewig, U. Distler, J. Haier, A. Denz, C. Pilarsky, N. Senninger, K. Dreisewerd, J. Peter-Katalinic, J. Muthing: Differences in CD75s- and iso-CD75s-ganglioside content and altered mRNA expression of sialyltransferases ST6GAL1 and ST3GAL6 in human hepatocellular carcinoma and non-tumoral liver tissues. Glycobiology (2010).

118. M. A. Recchi, M. Hebbar, L. Hornez, A. Harduin-Lepers, J. P. Peyrat, P. Delannoy: Multiplex reverse transcription polymerase chain reaction assessment of sialyltransferase expression in human breast cancer. Cancer Res 58, 4066-4070 (1998).
PMid:8748163

119. H. Yamamoto, Y. Kaneko, D. Vandermulen, D. Kersey, E. Mkrdichian, L. Cerullo, J. Leestma, J. R. Moskal: The expression of CMP-NeuAc: Gal b 1,4GlcNAc a 2,6 sialyltransferase (EC 2.4.99.1) and glycoproteins bearing a 2,6- linked sialic acids in human brain tumours. Glycoconj J 12, 848-856 (1995).
doi:10.1007/BF00731247
PMid:9331085

120. D. Pousset, V. Piller, N. Bureaud, M. Monsigny, F. Piller: Increased a2,6 sialylation of N-glycans in a transgenic mouse model of hepatocellular carcinoma. Cancer Res 57, 4249-4256 (1997).

121. F. Dall'Olio, N. Malagolini, F. Serafini-Cessi: Enhanced CMP-NeuAc:Gal b 1,4GlcNAc-R a2,6 sialyltransferase activity of human colon cancer xenografts in athymic nude mice and of xenograft-derived cell lines. Int J Cancer 50, 325-330 (1992).
doi:10.1002/ijc.2910500227

122. F. Dall'Olio, M. Chiricolo, P. Lollini, J. T. Lau: Human colon cancer cell lines permanently expressing a2,6- sialylated sugar chains by transfection with rat b-galactoside a 2,6 sialyltransferase cDNA. Biochem Biophys Res Commun 211, 554-561 (1995).
doi:10.1006/bbrc.1995.1849
PMid:11978012

123. S. Lin, W. Kemmner, S. Grigull, P. M. Schlag: Cell Surface a2,6-Sialylation Affects Adhesion of Breast Carcinoma Cells. Exp Cell Res 276, 101-110 (2002).
doi:10.1006/excr.2002.5521
PMid:15930282

124. E. C. Seales, G. A. Jurado, B. A. Brunson, J. K. Wakefield, A. R. Frost, S. L. Bellis: Hypersialylation of b1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility. Cancer Res 65, 4645-4652 (2005).
doi:10.1158/0008-5472.CAN-04-3117

125. H. Yamamoto, Y. Kaneko, A. Rebbaa, E. G. Bremer, J. R. Moskal: a2,6-Sialyltransferase gene transfection into a human glioma cell line (U373 MG) results in decreased invasivity. J Neurochem 68, 2566-2576 (1997).
doi:10.1046/j.1471-4159.1997.68062566.x
PMid:16192407

126. M. Chiricolo, N. Malagolini, S. Bonfiglioli, F. Dall'Olio: Phenotypic changes induced by expression of b-galactoside a2,6 sialyltransferase I in the human colon cancer cell line SW948. Glycobiology 16, 146-154 (2006).
doi:10.1093/glycob/cwj045
PMid:11559557

127. H. Yamamoto, A. Oviedo, C. Sweeley, T. Saito, J. R. Moskal: a2,6-Sialylation of cell-surface N-glycans inhibits glioma formation in vivo. Cancer Res 61, 6822-6829 (2001).
PMid:18199532

128. M. Hedlund, E. Ng, A. Varki, N. M. Varki: a2-6-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo. Cancer Res 68, 388-394 (2008).
doi:10.1158/0008-5472.CAN-07-1340
PMid:14562042

129. E. C. Seales, G. A. Jurado, A. Singhal, S. L. Bellis: Ras oncogene directs expression of a differentially sialylated, functionally altered b1 integrin. Oncogene 22, 7137-7145 (2003).
doi:10.1038/sj.onc.1206834
PMid:18703050    PMCid:2570357

130. F. M. Shaikh, E. C. Seales, W. C. Clem, K. M. Hennessy, Y. Zhuo, S. L. Bellis: Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms. Exp Cell Res 314, 2941-2950 (2008).
doi:10.1016/j.yexcr.2008.07.021
PMid:16157583

131. E. C. Seales, F. M. Shaikh, A. V. Woodard-Grice, P. Aggarwal, A. C. McBrayer, K. M. Hennessy, S. L. Bellis: A protein kinase C/Ras/ERK signaling pathway activates myeloid fibronectin receptors by altering b1 integrin sialylation. J Biol Chem 280, 37610-37615 (2005).
doi:10.1074/jbc.M508476200
PMid:12091385

132. A. C. Semel, E. C. Seales, A. Singhal, E. A. Eklund, K. J. Colley, S. L. Bellis: Hyposialylation of integrins stimulates the activity of myeloid fibronectin receptors. J Biol Chem 277, 32830-32836 (2002).
doi:10.1074/jbc.M202493200
PMid:20655849

133. D. PanY. Song: Role of altered sialylation of the I-like domain of b1 integrin in the binding of fibronectin to b1 integrin: thermodynamics and conformational analyses. Biophys J 99, 208-217 (2010).
doi:10.1016/j.bpj.2010.03.063
PMid:21173156

134. Y. ZhuoS. L. Bellis: Emerging Role of a2,6-Sialic Acid as a Negative Regulator of Galectin Binding and Function. J Biol Chem 286, 5935-5941 (2011).
doi:10.1074/jbc.R110.191429
PMid:18676377    PMCid:2494929

135. Y. Zhuo, R. Chammas, S. L. Bellis: Sialylation of b1 integrins blocks cell adhesion to galectin-3 and protects cells against galectin-3-induced apoptosis. J Biol Chem 283, 22177-22185 (2008).
doi:10.1074/jbc.M8000015200
PMid:16669711

136. W. J. Lee, Z. R. Majumder, D. I. Jeoung, H. J. Lee, S. H. Kim, S. Bae, Y. S. Lee: Organ-specific gene expressions in C57BL/6 mice after exposure to low-dose radiation. Radiat Res 165, 562-569 (2006).
doi:10.1667/RR3549.1
PMid:18708363

137. M. Lee, H. J. Lee, S. Bae, Y. S. Lee: Protein sialylation by sialyltransferase involves radiation resistance. Mol Cancer Res 6, 1316-1325 (2008).
doi:10.1158/1541-7786.MCR-07-2209
PMid:20338479

138. M. Lee, H. J. Lee, W. D. Seo, K. H. Park, Y. S. Lee: Sialylation of integrin b1 is involved in radiation-induced adhesion and migration in human colon cancer cells. Int J Radiat Oncol Biol Phys 76, 1528-1536 (2010).
doi:10.1016/j.ijrobp.2009.11.022
PMid:20127017

139. M. Lee, J. J. Park, Y. S. Lee: Adhesion of ST6Gal I-mediated human colon cancer cells to fibronectin contributes to cell survival by integrin b1-mediated paxillin and AKT activation. Oncol Rep 23, 757-761 (2010).
PMid:16024122

140. J. Seidler, R. Durzok, C. Brakebusch, N. Cordes: Interactions of the integrin subunit b1A with protein kinase B/Akt, p130Cas and paxillin contribute to regulation of radiation survival. Radiother Oncol 76, 129-134 (2005).
doi:10.1016/j.radonc.2005.06.018
PMid:10580130

141. I. Brockhausen: Pathways of O-glycan biosynthesis in cancer cells. Biochim Biophys Acta 1473, 67-95 (1999).
PMid:7734850

142. J. M. Yang, J. C. Byrd, B. B. Siddiki, Y. S. Chung, M. Okuno, M. Sowa, Y. S. Kim, K. L. Matta, I. Brockhausen: Alterations of O-glycan biosynthesis in human colon cancer tissues. Glycobiology 4, 873-884 (1994).
doi:10.1093/glycob/4.6.873
PMid:18339842

143. T. Ju, G. S. Lanneau, T. Gautam, Y. Wang, B. Xia, S. R. Stowell, M. T. Willard, W. Wang, J. Y. Xia, R. E. Zuna, Z. Laszik, D. M. Benbrook, M. H. Hanigan, R. D. Cummings: Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer Res 68, 1636-1646 (2008).
doi:10.1158/0008-5472.CAN-07-2345
PMid:18695044    PMCid:2500138

144. T. Ju, R. P. Aryal, C. J. Stowell, R. D. Cummings: Regulation of protein O-glycosylation by the endoplasmic reticulum-localized molecular chaperone Cosmc. J Cell Biol 182, 531-542 (2008).
doi:10.1083/jcb.200711151
PMid:17517967    PMCid:2118614

145. G. An, B. Wei, B. Xia, J. M. McDaniel, T. Ju, R. D. Cummings, J. Braun, L. Xia: Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 204, 1417-1429 (2007).
doi:10.1084/jem.20061929
PMid:17457671

146. L. G. Yu: The oncofetal Thomsen-Friedenreich carbohydrate antigen in cancer progression. Glycoconj J 24, 411-420 (2007).
doi:10.1007/s10719-007-9034-3
PMid:3420374

147. M. F. Wolf, A. Ludwig, P. Fritz, K. Schumacher: Increased expression of Thomsen-Friedenreich antigens during tumor progression in breast cancer patients. Tumour Biol 9, 190-194 (1988).
doi:10.1159/000217561
PMid:9046061

148. F. G. HanischS. E. Baldus: The Thomsen-Friedenreich (TF) antigen: a critical review on the structural, biosynthetic and histochemical aspects of a pancarcinoma- associated antigen. Histol Histopathol 12, 263-281 (1997).
PMid:7588808

149. I. Brockhausen, J. M. Yang, J. Burchell, C. Whitehouse, J. Taylor-Papadimitriou: Mechanisms underlying aberrant glycosylation of MUC1 mucin in breast cancer cells. Eur J Biochem 233, 607-617 (1995).
doi:10.1111/j.1432-1033.1995.607_2.x
PMid:8969192

150. K. O. Lloyd, J. Burchell, V. Kudryashov, B. W. T. Yin, J. Taylor-Papadimitriou: Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. Demonstration of simpler and fewer glycan chains in tumor cells. J Biol Chem 271, 33325-33334 (1996).
doi:10.1074/jbc.271.52.33325
PMid:10673297    PMCid:1727852

151. S. R. Hull, A. Bright, K. L. Carraway, M. Abe, D. F. Hayes, D. W. Kufe: Oligosaccharide differences in the DF3 sialomucin antigen from normal human milk and the BT-20 human breast carcinoma cell line. Cancer Commun 1, 261-267 (1989).
PMid:2639730

152. A. Cazet, S. Julien, M. Bobowski, J. Burchell, P. Delannoy: Tumour-associated carbohydrate antigens in breast cancer. Breast Cancer Res 12, 204 (2010).
doi:10.1186/bcr2577
PMid:20550729    PMCid:2917018

153. S. H. Itzkowitz, M. Yuan, C. K. Montgomery, T. Kjeldsen, H. K. Takahashi, W. L. Bigbee, Y. S. Kim: Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res 49, 197-204 (1989).
PMid:2908846

154. T. F. Orntoft, N. Harving, N. C. Langkilde: O-linked mucin-type glycoproteins in normal and malignant colon mucosa: lack of T-antigen expression and accumulation of Tn and sialosyl-Tn antigens in carcinomas. Int J Cancer 45, 666-672 (1990).
doi:10.1002/ijc.2910450416

155. M. Yuan, S. H. Itzkowitz, C. R. Boland, Y. D. Kim, J. T. Tomita, A. Palekar, J. L. Bennington, B. F. Trump, Y. S. Kim: Comparison of T-antigen expression in normal, premalignant, and malignant human colonic tissue using lectin and antibody immunohistochemistry. Cancer Res 46, 4841-4847 (1986).
PMid:3731131

156. B. J. Campbell, I. A. Finnie, E. F. Hounsell, J. M. Rhodes: Direct demonstration of increased expression of Thomsen-Friedenreich (TF) antigen in colonic adenocarcinoma and ulcerative colitis mucin and its concealment in normal mucin. J Clin Invest 95, 571-576 (1995).
doi:10.1172/JCI117700
PMid:7860740    PMCid:295516

157. Y. Cao, U. R. Karsten, W. Liebrich, W. Haensch, G. F. Springer, P. M. Schlag: Expression of Thomsen-Friedenreich-related antigens in primary and metastatic colorectal carcinomas. A reevaluation. Cancer 76, 1700-1708 (1995).
doi:10.1002/1097-0142(19951115)76:10<1700::AID-CNCR2820761005>3.0.CO;2-Z

158. S. K. Khaldoyanidi, V. V. Glinsky, L. Sikora, A. B. Glinskii, V. V. Mossine, T. P. Quinn, G. V. Glinsky, P. Sriramarao: MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions. J Biol Chem 278, 4127-4134 (2003).
doi:10.1074/jbc.M209590200
PMid:12438311

159. Q. Zhao, M. Barclay, J. Hilkens, X. Guo, H. Barrow, J. M. Rhodes, L. G. Yu: Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer 9, 154 (2010).
doi:10.1186/1476-4598-9-154
PMid:20565834    PMCid:2911446

160. V. V. Glinsky, G. V. Glinsky, K. Rittenhouse-Olson, M. E. Huflejt, O. V. Glinskii, S. L. Deutscher, T. P. Quinn: The role of Thomsen-Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. Cancer Res 61, 4851-4857 (2001).
PMid:11406562

161. L. G. Yu, N. Andrews, Q. Zhao, D. McKean, J. F. Williams, L. J. Connor, O. V. Gerasimenko, J. Hilkens, J. Hirabayashi, K. Kasai, J. M. Rhodes: Galectin-3 Interaction with Thomsen-Friedenreich Disaccharide on Cancer-associated MUC1 Causes Increased Cancer Cell Endothelial Adhesion. J Biol Chem 282, 773-781 (2007).
doi:10.1074/jbc.M606862200
PMid:17090543

162. V. V. Glinsky, M. E. Huflejt, G. V. Glinsky, S. L. Deutscher, T. P. Quinn: Effects of Thomsen-Friedenreich antigen-specific peptide P-30 on b-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells. Cancer Res 60, 2584-2588 (2000).
PMid:10825125

163. J. Zou, V. V. Glinsky, L. A. Landon, L. Matthews, S. L. Deutscher: Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. Carcinogenesis 26, 309-318 (2005).
doi:10.1093/carcin/bgh329
PMid:15528216

164. O. V. Glinskii, J. R. Turk, K. J. Pienta, V. H. Huxley, V. V. Glinsky: Evidence of porcine and human endothelium activation by cancer-associated carbohydrates expressed on glycoproteins and tumour cells. J Physiol 554, 89-99 (2004).
doi:10.1113/jphysiol.2003.054783
PMid:14678494    PMCid:1664748

165. J. M. Rhodes, B. J. Campbell, L. G. Yu: Lectin-epithelial interactions in the human colon. Biochem Soc Trans 36, 1482-1486 (2008).
doi:10.1042/BST0361482
PMid:19021580

166. S. D. Ryder, M. R. Jacyna, A. J. Levi, P. M. Rizzi, J. M. Rhodes: Peanut ingestion increases rectal proliferation in individuals with mucosal expression of peanut lectin receptor. Gastroenterology 114, 44-49 (1998).
doi:10.1016/S0016-5085(98)70631-6

167. R. Singh, S. Subramanian, J. M. Rhodes, B. J. Campbell: Peanut lectin stimulates proliferation of colon cancer cells by interaction with glycosylated CD44v6 isoforms and consequential activation of c-Met and MAPK: functional implications for disease-associated glycosylation changes. Glycobiology 16, 594-601 (2006).
doi:10.1093/glycob/cwj108
PMid:16571666

168. L. G. Yu, B. Jansson, D. G. Fernig, J. D. Milton, J. A. Smith, O. V. Gerasimenko, M. Jones, J. M. Rhodes: Stimulation of proliferation in human colon cancer cells by human monoclonal antibodies against the TF antigen (galactose b1-3 N-acetyl-galactosamine). Int J Cancer 73, 424-431 (1997).
doi:10.1002/(SICI)1097-0215(19971104)73:3<424::AID-IJC18>3.0.CO;2-C

169. J. Sotiriadis, S. C. Shin, D. Yim, D. Sieber, Y. B. Kim: Thomsen-Friedenreich (T) antigen expression increases sensitivity of natural killer cell lysis of cancer cells. Int J Cancer 111, 388-397 (2004).
doi:10.1002/ijc.20274
PMid:15221966

170. Y. Xu, S. J. Gendler, A. Franco: Designer glycopeptides for cytotoxic T cell-based elimination of carcinomas. J Exp Med 199, 707-716 (2004).
doi:10.1084/jem.20031865
PMid:14993254    PMCid:2213299

171. Y. Xu, A. Sette, J. Sidney, S. J. Gendler, A. Franco: Tumor-associated carbohydrate antigens: a possible avenue for cancer prevention. Immunol Cell Biol 83, 440-448 (2005).
doi:10.1111/j.1440-1711.2005.01347.x
PMid:16033540

172. J. Heimburg, J. Yan, S. Morey, O. V. Glinskii, V. H. Huxley, L. Wild, R. Klick, R. Roy, V. V. Glinsky, K. Rittenhouse-Olson: Inhibition of spontaneous breast cancer metastasis by anti-Thomsen-Friedenreich antigen monoclonal antibody JAA-F11. Neoplasia 8, 939-948 (2006).
doi:10.1593/neo.06493
PMid:17132226    PMCid:1716011

173. J. Burchell, R. Poulsom, A. Hanby, C. Whitehouse, L. Cooper, H. Clausen, D. Miles, J. Taylor-Papadimitriou: An a2,3 sialyltransferase (ST3Gal I) is elevated in primary breast carcinomas. Glycobiology 9, 1307-1311 (1999).
doi:10.1093/glycob/9.12.1307
PMid:10561455

174. G. Picco, S. Julien, I. Brockhausen, R. Beatson, A. Antonopoulos, S. Haslam, U. Mandel, A. Dell, S. Pinder, J. Taylor-Papadimitriou, J. Burchell: Over-expression of ST3Gal-I promotes mammary tumorigenesis. Glycobiology 20, 1241-1250 (2010).
doi:10.1093/glycob/cwq085
PMid:20534593    PMCid:2934706

175. P. A. Videira, M. Correia, N. Malagolini, H. J. Crespo, D. Ligeiro, F. M. Calais, H. Trindade, F. Dall'Olio: ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines. BMC Cancer 9, 357 (2009).
doi:10.1186/1471-2407-9-357
PMid:19811634    PMCid:2763879

176. T. Conze, A. S. Carvalho, U. Landegren, R. Almeida, C. A. Reis, L. David, O. Soderberg: MUC2 mucin is a major carrier of the cancer-associated sialyl-Tn antigen in intestinal metaplasia and gastric carcinomas. Glycobiology 20, 199-206 (2010).
doi:10.1093/glycob/cwp161
PMid:19815850

177. Y. Cao, U. Karsten, G. Otto, P. Bannasch: Expression of MUC1, Thomsen-Friedenreich antigen, Tn, sialosyl-Tn, and a2,6-linked sialic acid in hepatocellular carcinomas and preneoplastic hepatocellular lesions. Virchows Arch 434, 503-509 (1999).
doi:10.1007/s004280050375
PMid:10394884

178. S. Itzkowitz, T. Kjeldsen, A. Friera, S. Hakomori, U. S. Yang, Y. S. Kim: Expression of Tn, sialosyl Tn, and T antigens in human pancreas. Gastroenterology 100, 1691-1700 (1991).
PMid:1850375

179. S. H. Cho, A. Sahin, G. N. Hortobagyi, W. N. Hittelman, K. Dhingra: Sialyl-Tn antigen expression occurs early during human mammary carcinogenesis and is associated with high nuclear grade and aneuploidy. Cancer Res 54, 6302-6305 (1994).
PMid:7987817

180. D. W. Miles, L. C. Happerfield, P. Smith, R. Gillibrand, L. G. Bobrow, W. M. Gregory, R. D. Rubens: Expression of sialyl-Tn predicts the effect of adjuvant chemotherapy in node-positive breast cancer. Br J Cancer 70, 1272-1275 (1994).
doi:10.1038/bjc.1994.486
PMid:7981088    PMCid:2033699

181. S. Itzkowitz: Carbohydrate changes in colon carcinoma. APMIS Suppl 27, 173-180 (1992).
PMid:1381596

182. S. H. Itzkowitz, E. J. Bloom, W. A. Kokal, G. Modin, S. Hakomori, Y. S. Kim: Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients. Cancer 66, 1960-1966 (1990).
doi:10.1002/1097-0142(19901101)66:9<1960::AID-CNCR2820660919>3.0.CO;2-X

183. S. Pinho, N. T. Marcos, B. Ferreira, A. S. Carvalho, M. J. Oliveira, F. Santos-Silva, A. Harduin-Lepers, C. A. Reis: Biological significance of cancer-associated sialyl-Tn antigen: modulation of malignant phenotype in gastric carcinoma cells. Cancer Lett 249, 157-170 (2007).
doi:10.1016/j.canlet.2006.08.010
PMid:16965854

184. D. H. DubeC. R. Bertozzi: Glycans in cancer and inflammation--potential for therapeutics and diagnostics. Nat Rev Drug Discov 4, 477-488 (2005).
doi:10.1038/nrd1751
PMid:15931257

185. M. M. FusterJ. D. Esko: The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer 5, 526-542 (2005).
doi:10.1038/nrc1649
PMid:16069816

186. S. Julien, G. Picco, R. Sewell, A. S. Vercoutter-Edouart, M. Tarp, D. Miles, H. Clausen, J. Taylor-Papadimitriou, J. M. Burchell: Sialyl-Tn vaccine induces antibody-mediated tumour protection in a relevant murine model. Br J Cancer 100, 1746-1754 (2009).
doi:10.1038/sj.bjc.6605083
PMid:19436292    PMCid:2695689

187. N. T. Marcos, S. Pinho, C. Grandela, A. Cruz, B. Samyn-Petit, A. Harduin-Lepers, R. Almeida, F. Silva, V. Morais, J. Costa, J. Kihlberg, H. Clausen, C. A. Reis: Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res 64, 7050-7057 (2004).
doi:10.1158/0008-5472.CAN-04-1921
PMid:15466199

188. M. Clement, J. Rocher, G. Loirand, J. Le Pendu: Expression of sialyl-Tn epitopes on b1 integrin alters epithelial cell phenotype, proliferation and haptotaxis. J Cell Sci 117, 5059-5069 (2004).
doi:10.1242/jcs.01350
PMid:15383613

189. S. Julien, C. Lagadec, M. A. Krzewinski-Recchi, G. Courtand, Bourhis Le, X, P. Delannoy: Stable expression of sialyl-Tn antigen in T47-D cells induces a decrease of cell adhesion and an increase of cell migration. Breast Cancer Res Treat 90, 77-84 (2005).
doi:10.1007/s10549-004-3137-3
PMid:15770530

190. S. Julien, E. Adriaenssens, K. Ottenberg, A. Furlan, G. Courtand, A. S. Vercoutter-Edouart, F. G. Hanisch, P. Delannoy, Bourhis Le, X: ST6GalNAc I expression in MDA-MB-231 breast cancer cells greatly modifies their O-glycosylation pattern and enhances their tumourigenicity. Glycobiology 16, 54-64 (2006).
doi:10.1093/glycob/cwj033
PMid:16135558

191. R. Singh, B. J. Campbell, L. G. Yu, D. G. Fernig, J. D. Milton, R. A. Goodlad, A. J. FitzGerald, J. M. Rhodes: Cell surface-expressed Thomsen-Friedenreich antigen in colon cancer is predominantly carried on high molecular weight splice variants of CD44. Glycobiology 11, 587-592 (2001).
doi:10.1093/glycob/11.7.587
PMid:11447138

192. M. D. Burdick, A. Harris, C. J. Reid, T. Iwamura, M. A. Hollingsworth: Oligosaccharides expressed on MUC1 produced by pancreatic and colon tumor cell lines. J Biol Chem 272, 24198-24202 (1997).
doi:10.1074/jbc.272.39.24198
PMid:9305871

193. S. E. Baldus, F. G. Hanisch, G. M. Kotlarek, T. K. Zirbes, J. Thiele, J. Isenberg, U. R. Karsten, P. L. Devine, H. P. Dienes: Coexpression of MUC1 mucin peptide core and the Thomsen-Friedenreich antigen in colorectal neoplasms. Cancer 82, 1019-1027 (1998).
doi:10.1002/(SICI)1097-0142(19980315)82:6<1019::AID-CNCR3>3.0.CO;2-9

194. S. J. Storr, L. Royle, C. J. Chapman, U. M. Hamid, J. F. Robertson, A. Murray, R. A. Dwek, P. M. Rudd: The O-linked glycosylation of secretory/shed MUC1 from an advanced breast cancer patient's serum. Glycobiology 18, 456-462 (2008).
doi:10.1093/glycob/cwn022
PMid:18332077

195. I. Brockhausen, J. Yang, N. Dickinson, S. Ogata, S. H. Itzkowitz: Enzymatic basis for sialyl-Tn expression in human colon cancer cells. Glycoconj J 15, 595-603 (1998).
doi:10.1023/A:1006967910803
PMid:9881766

196. S. RuanK. O. Lloyd: Glycosylation pathways in the biosynthesis of gangliosides in melanoma and neuroblastoma cells: relative glycosyltransferase levels determine ganglioside patterns. Cancer Res 52, 5725-5731 (1992).
PMid:1394196

197. S. Ruan, B. K. Raj, K. O. Lloyd: Relationship of glycosyltransferases and mRNA levels to ganglioside expression in neuroblastoma and melanoma cells. J Neurochem 72, 514-521 (1999).
doi:10.1046/j.1471-4159.1999.0720514.x

198. I. J. Thampoe, K. Furukawa, E. Vellve, K. O. Lloyd: Sialyltransferase levels and ganglioside expression in melanoma and other cultured human cancer cells. Cancer Res 49, 6258-6264 (1989).
PMid:2804971

199. Z. L. Wu, E. Schwartz, R. Seeger, S. Ladisch: Expression of GD2 ganglioside by untreated primary human neuroblastomas. Cancer Res 46, 440-443 (1986).
PMid:3940209

200. A. R. TodeschiniS. I. Hakomori: Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780, 421-433 (2008).
PMid:17991443    PMCid:2312458

201. J. H. Finke, P. Rayman, R. George, C. S. Tannenbaum, V. Kolenko, R. Uzzo, A. C. Novick, R. M. Bukowski: Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor-kB suppression. Clin Cancer Res 7, 940s-946s (2001).
PMid:11300495

202. S. HakomoriK. Handa: Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to define tumor malignancy. FEBS Lett 531, 88-92 (2002).
doi:10.1016/S0014-5793(02)03479-8

203. L. M. Krug: Vaccine therapy for small cell lung cancer. Semin Oncol 31, 112-116 (2004).
doi:10.1053/j.seminoncol.2003.12.022
PMid:14981589

204. S. Birkle, L. Gao, G. Zeng, R. K. Yu: Down-regulation of GD3 ganglioside and its O-acetylated derivative by stable transfection with antisense vector against GD3-synthase gene expression in hamster melanoma cells: effects on cellular growth, melanogenesis, and dendricity. J Neurochem 74, 547-554 (2000).
doi:10.1046/j.1471-4159.2000.740547.x

205. K. Furukawa, K. Hamamura, H. Nakashima, K. Furukawa: Molecules in the signaling pathway activated by gangliosides can be targets of therapeutics for malignant melanomas. Proteomics 8, 3312-3316 (2008).
doi:10.1002/pmic.200800228
PMid:18690647

206. K. Ko, K. Furukawa, T. Takahashi, T. Urano, Y. Sanai, M. Nagino, Y. Nimura, K. Furukawa: Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers. Oncogene 25, 6924-6935 (2006).
doi:10.1038/sj.onc.1209683
PMid:16862187

207. Y. Miura, M. Kainuma, H. Jiang, H. Velasco, P. K. Vogt, S. Hakomori: Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside). Proc Natl Acad Sci U S A 101, 16204-16209 (2004).
doi:10.1073/pnas.0407297101
PMid:15534203    PMCid:528971

208. A. Prinetti, M. Aureli, G. Illuzzi, S. Prioni, V. Nocco, F. Scandroglio, N. Gagliano, G. Tredici, V. Rodriguez-Menendez, V. Chigorno, S. Sonnino: GM3 synthase overexpression results in reduced cell motility and in caveolin-1 upregulation in human ovarian carcinoma cells. Glycobiology 20, 62-77 (2010).
doi:10.1093/glycob/cwp143
PMid:19759399

209. P. Mukherjee, A. C. Faber, L. M. Shelton, R. C. Baek, T. C. Chiles, T. N. Seyfried: Thematic Review Series: Sphingolipids. Ganglioside GM3 suppresses the proangiogenic effects of vascular endothelial growth factor and ganglioside GD1a. J Lipid Res 49, 929-938 (2008).
doi:10.1194/jlr.R800006-JLR200
PMid:18287616    PMCid:2311436

210. Z. Wang, Z. Sun, A. V. Li, K. J. Yarema: Roles for UDP-GlcNAc 2-epimerase/ManNAc 6-kinase outside of sialic acid biosynthesis: modulation of sialyltransferase and BiP expression, GM3 and GD3 biosynthesis, proliferation, and apoptosis, and ERK1/2 phosphorylation. J Biol Chem 281, 27016-27028 (2006).
doi:10.1074/jbc.M604903200
PMid:16847058

211. J. Nakano, B. K. Raj, C. Asagami, K. O. Lloyd: Human melanoma cell lines deficient in GD3 ganglioside expression exhibit altered growth and tumorigenic characteristics. J Invest Dermatol 107, 543-548 (1996).
doi:10.1111/1523-1747.ep12582802
PMid:8823358

212. H. Sasaki, T. Momoi, C. Yamanaka, T. Yorifuji, M. Kaji, H. Mikawa: Changes in the ganglioside composition of human neuroblastoma cells under different growth conditions. Int J Cancer 47, 742-745 (1991).
doi:10.1002/ijc.2910470520

213. G. Zeng, D. D. Li, L. Gao, S. Birkle, E. Bieberich, A. Tokuda, R. K. Yu: Alteration of ganglioside composition by stable transfection with antisense vectors against GD3-synthase gene expression. Biochemistry 38, 8762-8769 (1999).
doi:10.1021/bi9906726
PMid:10393551

214. G. Zeng, L. Gao, R. K. Yu: Reduced cell migration, tumor growth and experimental metastasis of rat F-11 cells whose expression of GD3-synthase is suppressed. Int J Cancer 88, 53-57 (2000).
doi:10.1002/1097-0215(20001001)88:1<53::AID-IJC8>3.0.CO;2-7

215. G. Zeng, L. Gao, S. Birkle, R. K. Yu: Suppression of ganglioside GD3 expression in a rat F-11 tumor cell line reduces tumor growth, angiogenesis, and vascular endothelial growth factor production. Cancer Res 60, 6670-6676 (2000).
PMid:11118051

216. A. Cazet, J. Lefebvre, E. Adriaenssens, S. Julien, M. Bobowski, A. Grigoriadis, A. Tutt, D. Tulasne, Bourhis Le, X, P. Delannoy: GD3 synthase expression enhances proliferation and tumor growth of MDA-MB-231 breast cancer cells through c-Met activation. Mol Cancer Res 8, 1526-1535 (2010).
doi:10.1158/1541-7786.MCR-10-0302
PMid:20889649

217. X. Wang, P. Sun, A. Al Qamari, T. Tai, I. Kawashima, A. S. Paller: Carbohydrate-carbohydrate binding of ganglioside to integrin a5 modulates a5b1function. J Biol Chem 276, 8436-8444 (2001).
doi:10.1074/jbc.M006097200
PMid:11118433

218. K. Hamamura, K. Furukawa, T. Hayashi, T. Hattori, J. Nakano, H. Nakashima, T. Okuda, H. Mizutani, H. Hattori, M. Ueda, T. Urano, K. O. Lloyd, K. Furukawa: Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells. Proc Natl Acad Sci U S A 102, 11041-11046 (2005).
doi:10.1073/pnas.0503658102
PMid:16040804    PMCid:1180226

219. K. Hamamura, M. Tsuji, Y. Ohkawa, H. Nakashima, S. Miyazaki, T. Urano, N. Yamamoto, M. Ueda, K. Furukawa, K. Furukawa: Focal adhesion kinase as well as p130Cas and paxillin is crucially involved in the enhanced malignant properties under expression of ganglioside GD3 in melanoma cells. Biochim Biophys Acta 1780, 513-519 (2008).
PMid:18078823

220. S. Fukumoto, T. Mutoh, T. Hasegawa, H. Miyazaki, M. Okada, G. Goto, K. Furukawa, T. Urano: GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation. J Biol Chem 275, 5832-5838 (2000).
doi:10.1074/jbc.275.8.5832
PMid:10681573

221. H. Nakashima, K. Hamamura, T. Houjou, R. Taguchi, N. Yamamoto, K. Mitsudo, I. Tohnai, M. Ueda, T. Urano, K. Furukawa, K. Furukawa: Overexpression of caveolin-1 in a human melanoma cell line results in dispersion of ganglioside GD3 from lipid rafts and alteration of leading edges, leading to attenuation of malignant properties. Cancer Sci 98, 512-520 (2007).
doi:10.1111/j.1349-7006.2007.00419.x
PMid:17284246

222. N. Y. Kang, C. H. Kim, K. S. Kim, J. H. Ko, J. H. Lee, Y. K. Jeong, Y. C. Lee: Expression of the human CMP-NeuAc:GM3 a2,8-sialyltransferase (GD3 synthase) gene through the NF-kB activation in human melanoma SK-MEL-2 cells. Biochim Biophys Acta 1769, 622-630 (2007).
PMid:17913261

223. N. Y. Kang, S. K. Kang, Y. C. Lee, H. J. Choi, Y. S. Lee, S. Y. Cho, Y. S. Kim, J. H. Ko, C. H. Kim: Transcriptional regulation of the human GD3 synthase gene expression in Fas-induced Jurkat T cells: a critical role of transcription factor NF-kappaB in regulated expression. Glycobiology 16, 375-389 (2006).
doi:10.1093/glycob/cwj087
PMid:16481330

224. N. Hanai, G. A. Nores, C. MacLeod, C. R. Torres-Mendez, S. Hakomori: Ganglioside-mediated modulation of cell growth. Specific effects of GM3 and lyso-GM3 in tyrosine phosphorylation of the epidermal growth factor receptor. J Biol Chem 263, 10915-10921 (1988).
PMid:2839511

225. N. Kawashima, S. J. Yoon, K. Itoh, K. Nakayama: Tyrosine kinase activity of epidermal growth factor receptor is regulated by GM3 binding through carbohydrate to carbohydrate interactions. J Biol Chem 284, 6147-6155 (2009).
doi:10.1074/jbc.M808171200
PMid:19124464

226. S. J. Yoon, K. Nakayama, T. Hikita, K. Handa, S. I. Hakomori: Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor. Proc Natl Acad Sci U S A 103, 18987-18991 (2006).
doi:10.1073/pnas.0609281103
PMid:17142315    PMCid:1748164

227. T. W. Chung, S. J. Kim, H. J. Choi, K. J. Kim, M. J. Kim, S. H. Kim, H. J. Lee, J. H. Ko, Y. C. Lee, A. Suzuki, C. H. Kim: Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: direct interaction of GM3 with VEGFR-2. Glycobiology 19, 229-239 (2009).
doi:10.1093/glycob/cwn114
PMid:18974200

228. A. Sachinidis, R. Kraus, C. Seul, M. K. Meyer zu Brickwedde, K. Schulte, Y. Ko, J. Hoppe, H. Vetter: Gangliosides GM1, GM2 and GM3 inhibit the platelet-derived growth factor-induced signalling transduction pathway in vascular smooth muscle cells by different mechanisms. Eur J Cell Biol 71, 79-88 (1996).
PMid:8884181

229. E. Sottocornola, R. Misasi, V. Mattei, L. Ciarlo, R. Gradini, T. Garofalo, B. Berra, I. Colombo, M. Sorice: Role of gangliosides in the association of ErbB2 with lipid rafts in mammary epithelial HC11 cells. FEBS J 273, 1821-1830 (2006).
doi:10.1111/j.1742-4658.2006.05203.x
PMid:16623716

230. H. J. Choi, T. W. Chung, S. K. Kang, Y. C. Lee, J. H. Ko, J. G. Kim, C. H. Kim: Ganglioside GM3 modulates tumor suppressor PTEN-mediated cell cycle progression--transcriptional induction of p21(WAF1) and p27(kip1) by inhibition of PI-3K/AKT pathway. Glycobiology 16, 573-583 (2006).
doi:10.1093/glycob/cwj105
PMid:16574813

231. A. Hashiramoto, H. Mizukami, T. Yamashita: Ganglioside GM3 promotes cell migration by regulating MAPK and c-Fos/AP-1. Oncogene 25, 3948-3955 (2006).
doi:10.1038/sj.onc.1209416
PMid:16491123

232. H. Sohn, Y. S. Kim, H. T. Kim, C. H. Kim, E. W. Cho, H. Y. Kang, N. S. Kim, C. H. Kim, S. E. Ryu, J. H. Lee, J. H. Ko: Ganglioside GM3 is involved in neuronal cell death. FASEB J 20, 1248-1250 (2006).
doi:10.1096/fj.05-4911fje
PMid:16636105

233. A. R. Todeschini, J. N. Dos Santos, K. Handa, S. I. Hakomori: Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosynapse. J Biol Chem 282, 8123-8133 (2007).
doi:10.1074/jbc.M611407200
PMid:17215249

234. A. R. Todeschini, J. N. Dos Santos, K. Handa, S. I. Hakomori: Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc Natl Acad Sci U S A 105, 1925-1930 (2008).
doi:10.1073/pnas.0709619104
PMid:18272501    PMCid:2538860

235. Y. Liu, S. Yan, A. Wondimu, D. Bob, M. Weiss, K. Sliwinski, J. Villar, V. Notario, M. Sutherland, A. M. Colberg-Poley, S. Ladisch: Ganglioside synthase knockout in oncogene-transformed fibroblasts depletes gangliosides and impairs tumor growth. Oncogene 29, 3297-3306 (2010).
doi:10.1038/onc.2010.85
PMid:20305696    PMCid:2880627

236. M. Noguchi, K. Kabayama, S. Uemura, B. W. Kang, M. Saito, Y. Igarashi, J. Inokuchi: Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells. Glycobiology 16, 641-650 (2006).
doi:10.1093/glycob/cwj103
PMid:16571667

237. X. Q. Wang, P. Sun, L. Go, V. Koti, M. Fliman, A. S. Paller: Ganglioside GM3 Promotes Carcinoma Cell Proliferation via Urokinase Plasminogen Activator-Induced Extracellular Signal-Regulated Kinase-Independent p70S6 Kinase Signaling. J Invest Dermatol 126, 2687-2696 (2006).
doi:10.1038/sj.jid.5700469
PMid:16826166

238. S. K. Moon, H. M. Kim, Y. C. Lee, C. H. Kim: Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. J Biol Chem 279, 33063-33070 (2004).
doi:10.1074/jbc.M313462200
PMid:15175338

239. R. A. Kroes, H. He, M. R. Emmett, C. L. Nilsson, F. E. Leach, III, I. J. Amster, A. G. Marshall, J. R. Moskal: Overexpression of ST6GalNAcV, a ganglioside-specific a2,6-sialyltransferase, inhibits glioma growth in vivo. Proc Natl Acad Sci U S A 107, 12646-12651 (2010).
doi:10.1073/pnas.0909862107
PMid:20616019    PMCid:2906591

240. T. Miyagi, T. Wada, K. Yamaguchi, K. Shiozaki, I. Sato, Y. Kakugawa, H. Yamanami, T. Fujiya: Human sialidase as a cancer marker. Proteomics 8, 3303-3311 (2008).
doi:10.1002/pmic.200800248
PMid:18651674

241. T. Kato, Y. Wang, K. Yamaguchi, C. M. Milner, R. Shineha, S. Satomi, T. Miyagi: Overexpression of lysosomal-type sialidase leads to suppression of metastasis associated with reversion of malignant phenotype in murine B16 melanoma cells. Int J Cancer 92, 797-804 (2001).
doi:10.1002/ijc.1268
PMid:11351298

242. M. Sawada, S. Moriya, S. Saito, R. Shineha, S. Satomi, T. Yamori, T. Tsuruo, R. Kannagi, T. Miyagi: Reduced sialidase expression in highly metastatic variants of mouse colon adenocarcinoma 26 and retardation of their metastatic ability by sialidase overexpression. Int J Cancer 97, 180-185 (2002).
doi:10.1002/ijc.1598
PMid:11774262

243. T. Wada, K. Hata, K. Yamaguchi, K. Shiozaki, K. Koseki, S. Moriya, T. Miyagi: A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells. Oncogene 26, 2483-2490 (2007).
doi:10.1038/sj.onc.1210341
PMid:17334392

244. Y. Kakugawa, T. Wada, K. Yamaguchi, H. Yamanami, K. Ouchi, I. Sato, T. Miyagi: Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression. Proc Natl Acad Sci U S A 99, 10718-10723 (2002).
doi:10.1073/pnas.152597199
PMid:12149448    PMCid:125023

245. N. Papini, L. Anastasia, C. Tringali, G. Croci, R. Bresciani, K. Yamaguchi, T. Miyagi, A. Preti, A. Prinetti, S. Prioni, S. Sonnino, G. Tettamanti, B. Venerando, E. Monti: The Plasma Membrane-associated Sialidase MmNEU3 Modifies the Ganglioside Pattern of Adjacent Cells Supporting Its Involvement in Cell-to-Cell Interactions. J Biol Chem 279, 16989-16995 (2004).
doi:10.1074/jbc.M400881200
PMid:14970224

246. S. Ogata, I. Ho, A. Chen, D. Dubois, J. Maklansky, A. Singhal, S. Hakomori, S. H. Itzkowitz: Tumor-associated sialylated antigens are constitutively expressed in normal human colonic mucosa. Cancer Res 55, 1869-1874 (1995).
PMid:7537175

247. B. Mann, E. Klussmann, V. Vandamme-Feldhaus, M. Iwersen, M. L. Hanski, E. O. Riecken, H. J. Buhr, R. Schauer, Y. S. Kim, C. Hanski: Low O-acetylation of sialyl-Le(x) contributes to its overexpression in colon carcinoma metastases. Int J Cancer 72, 258-264 (1997).
doi:10.1002/(SICI)1097-0215(19970717)72:2<258::AID-IJC10>3.0.CO;2-C

248. K. Kumamoto, Y. Goto, K. Sekikawa, S. Takenoshita, N. Ishida, M. Kawakita, R. Kannagi: Increased expression of UDP-galactose transporter messenger RNA in human colon cancer tissues and its implication in synthesis of Thomsen- Friedenreich antigen and sialyl Lewis A/X determinants. Cancer Res 61, 4620-4627 (2001).
PMid:11389099

249. J. Yin, A. Hashimoto, M. Izawa, K. Miyazaki, G. Y. Chen, H. Takematsu, Y. Kozutsumi, A. Suzuki, K. Furuhata, F. L. Cheng, C. H. Lin, C. Sato, K. Kitajima, R. Kannagi: Hypoxic culture induces expression of sialin, a sialic acid transporter, and cancer-associated gangliosides containing non-human sialic acid on human cancer cells. Cancer Res 66, 2937-2945 (2006).
doi:10.1158/0008-5472.CAN-05-2615
PMid:16540641

250. A. Yusa, K. Miyazaki, N. Kimura, M. Izawa, R. Kannagi: Epigenetic silencing of the sulfate transporter gene DTDST induces sialyl Lewisx expression and accelerates proliferation of colon cancer cells. Cancer Res 70, 4064-4073 (2010).
doi:10.1158/0008-5472.CAN-09-2383
PMid:20460514

251. J. Gu, Y. Sato, Y. Kariya, T. Isaji, N. Taniguchi, T. Fukuda: A mutual regulation between cell-cell adhesion and N-glycosylation: implication of the bisecting GlcNAc for biological functions. J Proteome Res 8, 431-435 (2009).
doi:10.1021/pr800674g
PMid:19053837

252. K. Sasai, Y. Ikeda, H. Eguchi, T. Tsuda, K. Honke, N. Taniguchi: The action of N-acetylglucosaminyltransferase-V is prevented by the bisecting GlcNAc residue at the catalytic step. FEBS Lett 522, 151-155 (2002).
doi:10.1016/S0014-5793(02)02916-2

253. Y. Zhao, T. Nakagawa, S. Itoh, K. Inamori, T. Isaji, Y. Kariya, A. Kondo, E. Miyoshi, K. Miyazaki, N. Kawasaki, N. Taniguchi, J. Gu: N-acetylglucosaminyltransferase III antagonizes the effect of N-acetylglucosaminyltransferase V on a3b1 integrin-mediated cell migration. J Biol Chem 281, 32122-32130 (2006).
doi:10.1074/jbc.M607274200
PMid:16940045

254. T. Isaji, J. Gu, R. Nishiuchi, Y. Zhao, M. Takahashi, E. Miyoshi, K. Honke, K. Sekiguchi, N. Taniguchi: Introduction of bisecting GlcNAc into integrin a5b1 reduces ligand binding and down-regulates cell adhesion and cell migration. J Biol Chem 279, 19747-19754 (2004).
doi:10.1074/jbc.M311627200
PMid:14998999

255. A. Rebbaa, H. Yamamoto, T. Saito, E. Meuillet, P. Kim, D. S. Kersey, E. G. Bremer, N. Taniguchi, J. R. Moskal: Gene transfection-mediated overexpression of b1,4-N- acetylglucosamine bisecting oligosaccharides in glioma cell line U373 MG inhibits epidermal growth factor receptor function. J Biol Chem 272, 9275-9279 (1997).
doi:10.1074/jbc.272.14.9275
PMid:9083062

256. S. S. Pinho, R. Seruca, F. Gartner, Y. Yamaguchi, J. Gu, N. Taniguchi, C. A. Reis: Modulation of E-cadherin function and dysfunction by N-glycosylation. Cell Mol Life Sci 68, 1011-1020 (2011).
doi:10.1007/s00018-010-0595-0
PMid:21104290

257. Y. Zhao, Y. Sato, T. Isaji, T. Fukuda, A. Matsumoto, E. Miyoshi, J. Gu, N. Taniguchi: Branched N-glycans regulate the biological functions of integrins and cadherins. FEBS J 275, 1939-1948 (2008).
doi:10.1111/j.1742-4658.2008.06346.x
PMid:18384383

258. T. Kitada, E. Miyoshi, K. Noda, S. Higashiyama, H. Ihara, N. Matsuura, N. Hayashi, S. Kawata, Y. Matsuzawa, N. Taniguchi: The addition of bisecting N-acetylglucosamine residues to E-cadherin down-regulates the tyrosine phosphorylation of beta-catenin. J Biol Chem 276, 475-480 (2001).
doi:10.1074/jbc.M006689200
PMid:11024053

259. M. Yoshimura, A. Nishikawa, Y. Ihara, S. Taniguchi, N. Taniguchi: Suppression of lung metastasis of B16 mouse melanoma by N-acetylglucosaminyltransferase III gene transfection. Proc Natl Acad Sci U S A 92, 8754-8758 (1995).
doi:10.1073/pnas.92.19.8754

260. Q. Xu, R. Akama, T. Isaji, Y. Lu, H. Hashimoto, Y. Kariya, T. Fukuda, Y. Du, J. Gu: Wnt/b-Catenin Signaling Down-regulates N-Acetylglucosaminyltransferase III Expression: the implications of two mutually exclusive pathways for regulation. J Biol Chem 286, 4310-4318 (2011).
doi:10.1074/jbc.M110.182576
PMid:21115490

261. Y. Sheng, M. Yoshimura, S. Inoue, K. Oritani, T. Nishiura, H. Yoshida, M. Ogawa, Y. Okajima, Y. Matsuzawa, N. Taniguchi: Remodeling of glycoconjugates on CD44 enhances cell adhesion to hyaluronate, tumor growth and metastasis in B16 melanoma cells expressing b1,4-N-acetylglucosaminyltransferase III. Int J Cancer 73, 850-858 (1997).
doi:10.1002/(SICI)1097-0215(19971210)73:6<850::AID-IJC15>3.0.CO;2-8

262. X. Yang, J. Tang, C. E. Rogler, P. Stanley: Reduced hepatocyte proliferation is the basis of retarded liver tumor progression and liver regeneration in mice lacking N-acetylglucosaminyltransferase III. Cancer Res 63, 7753-7759 (2003).
PMid:14633700

263. R. Kannagi: Carbohydrate antigen sialyl Lewis a--its pathophysiological significance and induction mechanism in cancer progression. Chang Gung Med J 30, 189-209 (2007).
PMid:17760270

264. K. Miyazaki, K. Ohmori, M. Izawa, T. Koike, K. Kumamoto, K. Furukawa, T. Ando, M. Kiso, T. Yamaji, Y. Hashimoto, A. Suzuki, A. Yoshida, M. Takeuchi, R. Kannagi: Loss of disialyl Lewisa the ligand for lymphocyte inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) associated with increased sialyl Lewis a expression on human colon cancers. Cancer Res 64, 4498-4505 (2004).
doi:10.1158/0008-5472.CAN-03-3614
PMid:15231659

265. A. Tsuchida, T. Okajima, K. Furukawa, T. Ando, H. Ishida, A. Yoshida, Y. Nakamura, R. Kannagi, M. Kiso, K. Furukawa: Synthesis of disialyl Lewis a (Lea) structure in colon cancer cell lines by a sialyltransferase, ST6GalNAc VI, responsible for the synthesis of a-series gangliosides. J Biol Chem 278, 22787-22794 (2003).
doi:10.1074/jbc.M211034200
PMid:12668675

266. C. Robbe-Masselot, A. Herrmann, E. Maes, I. Carlstedt, J. C. Michalski, C. Capon: Expression of a core 3 disialyl-Lex hexasaccharide in human colorectal cancers: a potential marker of malignant transformation in colon. J Proteome Res 8, 702-711 (2009).
doi:10.1021/pr800740j
PMid:19152289

267. F. Serafini-CessiF. Dall'Olio: Guinea-pig kidney b-N-acetylgalactosaminyltransferase towards Tamm- Horsfall glycoprotein. Requirement of sialic acid in the acceptor for transferase activity. Biochem J 215, 483-489 (1983).
PMid:6229247    PMCid:1152427

268. T. Dohi, Y. Yuyama, Y. Natori, P. L. Smith, J. B. Lowe, M. Oshima: Detection of N-acetylgalactosaminyltransferase mRNA which determines expression of Sda blood group carbohydrate structure in human gastrointestinal mucosa and cancer. Int J Cancer 67, 626-631 (1996).
doi:10.1002/(SICI)1097-0215(19960904)67:5<626::AID-IJC6>3.0.CO;2-W

269. N. Malagolini, F. Dall'Olio, G. Di Stefano, F. Minni, D. Marrano, F. Serafini-Cessi: Expression of UDP-GalNAc:NeuAc a2,3Gal b-R beta 1,4(GalNAc to Gal) N-acetylgalactosaminyltransferase involved in the synthesis of Sda antigen in human large intestine and colorectal carcinomas. Cancer Res 49, 6466-6470 (1989).
PMid:2510926

270. C. Capon, E. Maes, J. C. Michalski, H. Leffler, Y. S. Kim: Sda-antigen-like structures carried on core 3 are prominent features of glycans from the mucin of normal human descending colon. Biochem J 358, 657-664 (2001).
PMid:11577689    PMCid:1222115

271. S. Mathieu, M. Prorok, A. M. Benoliel, R. Uch, C. Langlet, P. Bongrand, R. Gerolami, A. El Battari: Transgene Expression of a(1,2)-Fucosyltransferase-I (FUT1) in Tumor Cells Selectively Inhibits Sialyl-Lewis x Expression and Binding to E-Selectin without Affecting Synthesis of Sialyl-Lewis a or Binding to P-Selectin. Am J Pathol 164, 371-383 (2004).
doi:10.1016/S0002-9440(10)63127-6

272. M. Aubert, L. Panicot, C. Crotte, P. Gibier, D. Lombardo, M. O. Sadoulet, E. Mas: Restoration of a1,2 fucosyltransferase activity decreases adhesive and metastatic properties of human pancreatic cancer cells. Cancer Res 60, 1449-1456 (2000).
PMid:10728712

273. M. Dalziel, C. Whitehouse, I. McFarlane, I. Brockhausen, S. Gschmeissner, T. Schwientek, H. Clausen, J. M. Burchell, J. Taylor-Papadimitriou: The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J Biol Chem 276, 11007-11015 (2001).
doi:10.1074/jbc.M006523200
PMid:11118434

274. F. Schneider, W. Kemmner, W. Haensch, G. Franke, S. Gretschel, U. Karsten, P. M. Schlag: Overexpression of sialyltransferase CMP-sialic acid:Galb1,3GalNAc-R a6-Sialyltransferase is related to poor patient survival in human colorectal carcinomas. Cancer Res 61, 4605-4611 (2001).
PMid:11389097

275. I. Brockhausen, J. Yang, M. Lehotay, S. Ogata, S. Itzkowitz: Pathways of mucin O-glycosylation in normal and malignant rat colonic epithelial cells reveal a mechanism for cancer-associated Sialyl-Tn antigen expression. Biol Chem 382, 219-232 (2001).
doi:10.1515/BC.2001.029
PMid:11308020

276. J. G. Collard, W. P. van Beek, J. W. Janssen, J. F. Schijven: Transfection by human oncogenes: concomitant induction of tumorigenicity and tumor-associated membrane alterations. Int J Cancer 35, 207-213 (1985).
doi:10.1002/ijc.2910350211

277. U. V. Santer, F. Gilbert, M. C. Glick: Change in glycosylation of membrane glycoproteins after transfection of NIH 3T3 with human tumor DNA. Cancer Res 44, 3730-3735 (1984).
PMid:6744291

278. J. W. Dennis, K. Kosh, D. M. Bryce, M. L. Breitman: Oncogenes conferring metastatic potential induce increased branching of Asn-linked oligosaccharides in rat2 fibroblasts. Oncogene 4, 853-860 (1989).
PMid:2666906

279. M. PierceJ. Arango: Rous sarcoma virus-transformed baby hamster kidney cells express higher levels of asparagine-linked tri- and tetraantennary glycopeptides containing (GlcNAc-b1,6Man-a1,6Man) and poly-N- acetyllactosamine sequences than baby hamster kidney cells. J Biol Chem 261, 10772-10777 (1986).
PMid:3015940

280. K. Yamashita, T. Ohkura, Y. Tachibana, S. Takasaki, A. Kobata: Comparative study of the oligosaccharides released from baby hamster kidney cells and their polyoma transformant by hydrazinolysis. J Biol Chem 259, 10834-10840 (1984).
PMid:6088518

281. P. Buckhaults, L. Chen, N. Fregien, M. Pierce: Transcriptional regulation of N-acetylglucosaminyltransferase V by the src oncogene. J Biol Chem 272, 19575-19581 (1997).
doi:10.1074/jbc.272.31.19575
PMid:9235963

282. L. Chen, W. Zhang, N. Fregien, M. Pierce: The her-2/neu oncogene stimulates the transcription of N- acetylglucosaminyltransferase V and expression of its cell surface oligosaccharide products. Oncogene 17, 2087-2093 (1998).
doi:10.1038/sj.onc.1202124
PMid:9798679

283. H. B. Guo, Q. S. Zhang, H. L. Chen: Effects of H-ras and v-sis overexpression on N- acetylglucosaminyltransferase V and metastasis-related phenotypes in human hepatocarcinoma cells. J Cancer Res Clin Oncol 126, 263-270 (2000).
doi:10.1007/s004320050341
PMid:10815761

284. Y. LuW. Chaney: Induction of N-acetylglucosaminyltransferase V by elevated expression of activated or proto-Ha-ras oncogenes. Mol Cell Biochem 122, 85-92 (1993).
doi:10.1007/BF00925741
PMid:8350868

285. D. C. Wojciechowicz, P. Y. Park, R. V. Datta, P. B. Paty: CEA is the major PHA-L-reactive glycoprotein in colon carcinoma cell lines and tumors: relationship between K-ras activation and b1-6 branching of N-linked carbohydrate on CEA. Biochem Biophys Res Commun 273, 147-153 (2000).
doi:10.1006/bbrc.2000.2906
PMid:10873577

286. R. Kang, H. Saito, Y. Ihara, E. Miyoshi, N. Koyama, Y. Sheng, N. Taniguchi: Transcriptional regulation of the N-acetylglucosaminyltransferase V gene in human bile duct carcinoma cells (HuCC-T1) is mediated by Ets-1. J Biol Chem 271, 26706-26712 (1996).
doi:10.1074/jbc.271.43.26706
PMid:8900148

287. J. H. Ko, E. Miyoshi, K. Noda, A. Ekuni, R. Kang, Y. Ikeda, N. Taniguchi: Regulation of the GnT-V promoter by transcription factor Ets-1 in various cancer cell lines. J Biol Chem 274, 22941-22948 (1999).
doi:10.1074/jbc.274.33.22941
PMid:10438459

288. M. Dalziel, F. Dall'Olio, A. Mungul, V. Piller, F. Piller: Ras oncogene induces b-galactoside a2,6-sialyltransferase (ST6Gal I) via a RalGEF-mediated signal to its housekeeping promoter. Eur J Biochem 271, 3623-3634 (2004).
doi:10.1111/j.1432-1033.2004.04284.x
PMid:15355339

289. P. Delannoy, H. Pelczar, V. Vandamme, A. Verbert: Sialyltransferase activity in FR3T3 cells transformed with ras oncogene: decreased CMP-Neu5Ac:Gal b1-3GalNAc a-2,3- sialyltransferase. Glycoconj J 10, 91-98 (1993).
doi:10.1007/BF00731192
PMid:8358231

290. E. W. Easton, J. G. Bolscher, D. H. van den Eijnden: Enzymatic amplification involving glycosyltransferases forms the basis for the increased size of asparagine-linked glycans at the surface of NIH 3T3 cells expressing the N-ras proto-oncogene. J Biol Chem 266, 21674-21680 (1991).
PMid:1657976

291. N. Le Marer, V. Laudet, E. C. Svensson, H. Cazlaris, B. Van Hille, C. Lagrou, D. Stehelin, J. Montreuil, A. Verbert, P. Delannoy: The c-Ha-ras oncogene induces increased expression of b-galactoside a-2, 6-sialyltransferase in rat fibroblast (FR3T3) cells. Glycobiology 2, 49-56 (1992).
doi:10.1093/glycob/2.1.49
PMid:1550989

292. X. Zhu, J. Jiang, H. Shen, H. Wang, H. Zong, Z. Li, Y. Yang, Z. Niu, W. Liu, X. Chen, Y. Hu, J. Gu: Elevated b1,4-galactosyltransferase I in highly metastatic human lung cancer cells. Identification of E1AF as important transcription activator. J Biol Chem 280, 12503-12516 (2005).
doi:10.1074/jbc.M413631200
PMid:15611127

293. T. SatoK. Furukawa: Sequential action of Ets-1 and Sp1 in the activation of the human b-1,4-galactosyltransferase V gene involved in abnormal glycosylation characteristic of cancer cells. J Biol Chem 282, 27702-27712 (2007).
doi:10.1074/jbc.M611862200
PMid:17656364

294. S. Andre, H. Sanchez-Ruderisch, H. Nakagawa, M. Buchholz, J. Kopitz, P. Forberich, W. Kemmner, C. Bock, K. Deguchi, K. M. Detjen, B. Wiedenmann, Doeberitz M. von Knebel, T. M. Gress, S. Nishimura, S. Rosewicz, H. J. Gabius: Tumor suppressor p16 INK4a modulator of glycomic profile and galectin-1 expression to increase susceptibility to carbohydrate-dependent induction of anoikis in pancreatic carcinoma cells. FEBS J 274, 3233-3256 (2007).
doi:10.1111/j.1742-4658.2007.05851.x
PMid:17535296

295. H. Sanchez-Ruderisch, K. M. Detjen, M. Welzel, S. Andre, C. Fischer, H. J. Gabius, S. Rosewicz: Galectin-1 sensitizes carcinoma cells to anoikis via the fibronectin receptor a5b1-integrin. Cell Death Differ (2010).

296. H. Sanchez-Ruderisch, C. Fischer, K. M. Detjen, M. Welzel, A. Wimmel, J. C. Manning, S. Andre, H. J. Gabius: Tumor suppressor p16INK4a: Downregulation of galectin-3, an endogenous competitor of the pro-anoikis effector galectin-1, in a pancreatic carcinoma model. FEBS J 277, 3552-3563 (2010).
doi:10.1111/j.1742-4658.2010.07764.x
PMid:20695889

297. A. Paz, R. Haklai, G. Elad-Sfadia, E. Ballan, Y. Kloog: Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20, 7486-7493 (2001).
doi:10.1038/sj.onc.1204950
PMid:11709720

298. G. Elad-Sfadia, R. Haklai, E. Balan, Y. Kloog: Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J Biol Chem 279, 34922-34930 (2004).
doi:10.1074/jbc.M312697200
PMid:15205467

299. V. L. Thijssen, B. Barkan, H. Shoji, I. M. Aries, V. Mathieu, L. Deltour, T. M. Hackeng, R. Kiss, Y. Kloog, F. Poirier, A. W. Griffioen: Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70, 6216-6224 (2010).
doi:10.1158/0008-5472.CAN-09-4150
PMid:20647324

300. V. Balan, P. Nangia-Makker, Y. S. Jung, Y. Wang, A. Raz: Galectin-3: A novel substrate for c-Abl kinase. Biochim Biophys Acta 1803, 1198-1205 (2010).
doi:10.1016/j.bbamcr.2010.06.007
PMid:20600357

301. H. B. Guo, F. Liu, J. H. Zhao, H. L. Chen: Down-regulation of N-acetylglucosaminyltransferase V by tumorigenesis- or metastasis-suppressor gene and its relation to metastatic potential of human hepatocarcinoma cells. J Cell Biochem 79, 370-385 (2000).
doi:10.1002/1097-4644(20001201)79:3<370::AID-JCB30>3.0.CO;2-Z

302. L. L. Duan, P. Guo, Y. Zhang, H. L. Chen: Regulation of metastasis-suppressive gene Nm23-H1 on glycosyl-transferases involved in the synthesis of sialyl Lewis antigens. J Cell Biochem 94, 1248-1257 (2005).
doi:10.1002/jcb.20346
PMid:15696547

303. S. She, B. Xu, M. He, X. Lan, Q. Wang: Nm23-H1 suppresses hepatocarcinoma cell adhesion and migration on fibronectin by modulating glycosylation of integrin b1. J Exp Clin Cancer Res 29, 93 (2010).
doi:10.1186/1756-9966-29-93

304. A. WeidemannR. S. Johnson: Biology of HIF-1a. Cell Death Differ 15, 621-627 (2008).
doi:10.1038/cdd.2008.12
PMid:18259201

305. R. Kannagi, K. Sakuma, K. Miyazaki, K. T. Lim, A. Yusa, J. Yin, M. Izawa: Altered expression of glycan genes in cancers induced by epigenetic silencing and tumor hypoxia: clues in the ongoing search for new tumor markers. Cancer Sci 101, 586-593 (2010).
doi:10.1111/j.1349-7006.2009.01455.x
PMid:20085584

306. T. Koike, N. Kimura, K. Miyazaki, T. Yabuta, K. Kumamoto, S. Takenoshita, J. Chen, M. Kobayashi, M. Hosokawa, A. Taniguchi, T. Kojima, N. Ishida, M. Kawakita, H. Yamamoto, H. Takematsu, A. Suzuki, Y. Kozutsumi, R. Kannagi: Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates. Proc Natl Acad Sci U S A 101, 8132-8137 (2004).
doi:10.1073/pnas.0402088101
PMid:15141079    PMCid:419569

307. P. Tangvoranuntakul, P. Gagneux, S. Diaz, M. Bardor, N. Varki, A. Varki, E. Muchmore: Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid. Proc Natl Acad Sci U S A 100, 12045-12050 (2003).
doi:10.1073/pnas.2131556100
PMid:14523234    PMCid:218710

308. J. Yin, K. Miyazaki, R. L. Shaner, A. H. Merrill, Jr., R. Kannagi: Altered sphingolipid metabolism induced by tumor hypoxia - new vistas in glycolipid tumor markers. FEBS Lett 584, 1872-1878 (2010).
doi:10.1016/j.febslet.2009.11.019
PMid:19913543

309. Q. T. Le, G. Shi, H. Cao, D. W. Nelson, Y. Wang, E. Y. Chen, S. Zhao, C. Kong, D. Richardson, K. J. O'byrne, A. J. Giaccia, A. C. Koong: Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 23, 8932-8941 (2005).
doi:10.1200/JCO.2005.02.0206
PMid:16219933

310. N. L. Perillo, K. E. Pace, J. J. Seilhamer, L. G. Baum: Apoptosis of T cells mediated by galectin-1. Nature 378, 736-739 (1995).
doi:10.1038/378736a0
PMid:7501023

311. X. Y. Zhao, T. T. Chen, L. Xia, M. Guo, Y. Xu, F. Yue, Y. Jiang, G. Q. Chen, K. W. Zhao: Hypoxia inducible factor-1 mediates expression of galectin-1: the potential role in migration/invasion of colorectal cancer cells. Carcinogenesis 31, 1367-1375 (2010).
doi:10.1093/carcin/bgq116
PMid:20525878

312. S. B. BaylinJ. E. Ohm: Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6, 107-116 (2006).
doi:10.1038/nrc1799
PMid:16491070

313. A. P. Feinberg, R. Ohlsson, S. Henikoff: The epigenetic progenitor origin of human cancer. Nat Rev Genet 7, 21-33 (2006).
doi:10.1038/nrg1748
PMid:16369569

314. Y. Hata, Y. Kominato, H. Takizawa: Identification and characterization of a novel antisense RNA transcribed from the opposite strand of the human blood group ABO gene. Transfusion 47, 842-851 (2007).
doi:10.1111/j.1537-2995.2007.01198.x
PMid:17465949

315. R. Murr: Interplay between different epigenetic modifications and mechanisms. Adv Genet 70, 101-141 (2010).
doi:10.1016/B978-0-12-380866-0.60005-8
PMid:20920747

316. Y. S. KimG. Deng: Aberrant expression of carbohydrate antigens in cancer: the role of genetic and epigenetic regulation. Gastroenterology 135, 305-309 (2008).
doi:10.1053/j.gastro.2008.06.013
PMid:18558094

317. H. Ahmed, P. P. Banerjee, G. R. Vasta: Differential expression of galectins in normal, benign and malignant prostate epithelial cells: Silencing of galectin-3 expression in prostate cancer by its promoter methylation. Biochem Biophys Res Commun 358, 241-246 (2007).
doi:10.1016/j.bbrc.2007.04.114
PMid:17481580

318. H. Ahmed, F. Cappello, V. Rodolico, G. R. Vasta: Evidence of heavy methylation in the galectin 3 promoter in early stages of prostate adenocarcinoma: development and validation of a methylated marker for early diagnosis of prostate cancer. Transl Oncol 2, 146-156 (2009).
PMid:19701499    PMCid:2730137

319. M. Demers, J. Couillard, G. Giglia-Mari, T. Magnaldo, Y. St Pierre: Increased galectin-7 gene expression in lymphoma cells is under the control of DNA methylation. Biochem Biophys Res Commun 387, 425-429 (2009).
doi:10.1016/j.bbrc.2009.07.015
PMid:19596268

320. P. Juszczynski, S. J. Rodig, J. Ouyang, E. O'Donnell, K. Takeyama, W. Mlynarski, K. Mycko, T. Szczepanski, A. Gaworczyk, A. Krivtsov, J. Faber, A. U. Sinha, G. A. Rabinovich, S. A. Armstrong, J. L. Kutok, M. A. Shipp: MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1. Clin Cancer Res 16, 2122-2130 (2010).
doi:10.1158/1078-0432.CCR-09-2765
PMid:20332322

321. K. H. Ruebel, L. Jin, X. Qian, B. W. Scheithauer, K. Kovacs, N. Nakamura, H. Zhang, A. Raz, R. V. Lloyd: Effects of DNA methylation on galectin-3 expression in pituitary tumors. Cancer Res 65, 1136-1140 (2005).
doi:10.1158/0008-5472.CAN-04-3578
PMid:15734994

322. V. Giordanengo, L. Ollier, M. Lanteri, J. Lesimple, D. March, S. Thyss, J. C. Lefebvre: Epigenetic reprogramming of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) in HIV-1-infected CEM T cells. FASEB J 18, 1961-1963 (2004).
PMid:15469965

323. C. Oetke, S. Hinderlich, W. Reutter, M. Pawlita: Epigenetically mediated loss of UDP-GlcNAc 2-epimerase/ManNAc kinase expression in hyposialylated cell lines. Biochem Biophys Res Commun 308, 892-898 (2003).
doi:10.1016/S0006-291X(03)01471-2

324. A. K. Chakraborty, Jde F. Sousa, D. Chakraborty, Y. Funasaka, M. Bhattacharya, A. Chatterjee, J. Pawelek: GnT-V expression and metastatic phenotypes in macrophage-melanoma fusion hybrids is down-regulated by 5-Aza-dC: evidence for methylation sensitive, extragenic regulation of GnT-V transcription. Gene 374, 166-173 (2006).
PMid:15615870

325. E. DabelsteenS. Gao: ABO blood-group antigens in oral cancer. J Dent Res 84, 21-28 (2005).
doi:10.1177/154405910508400103
PMid:14750174

326. S. Gao, J. Worm, P. Guldberg, H. Eiberg, A. Krogdahl, C. J. Liu, J. Reibel, E. Dabelsteen: Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma. Int J Cancer 109, 230-237 (2004).
doi:10.1002/ijc.11592
PMid:16434023

327. Y. Ide, E. Miyoshi, T. Nakagawa, J. Gu, M. Tanemura, T. Nishida, T. Ito, H. Yamamoto, Y. Kozutsumi, N. Taniguchi: Aberrant expression of N-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreatic cancer. Biochem Biophys Res Commun 341, 478-482 (2006).
doi:10.1016/j.bbrc.2005.12.208
PMid:18543267

328. T. Karibe, H. Fukui, A. Sekikawa, K. Shiratori, T. Fujimori: EXTL3 promoter methylation down-regulates EXTL3 and heparan sulphate expression in mucinous colorectal cancers. J Pathol 216, 32-42 (2008).
doi:10.1002/path.2377
PMid:18485915

329. Y. I. Kawamura, M. Toyota, R. Kawashima, T. Hagiwara, H. Suzuki, K. Imai, Y. Shinomura, T. Tokino, R. Kannagi, T. Dohi: DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Gastroenterology 135, 142-151 (2008).
doi:10.1053/j.gastro.2008.03.031
PMid:16427187

330. J. Serpa, P. Mesquita, N. Mendes, C. Oliveira, R. Almeida, F. Santos-Silva, C. A. Reis, J. Lependu, L. David: Expression of Le(a) in gastric cancer cell lines depends on FUT3 expression regulated by promoter methylation. Cancer Lett 242, 191-197 (2006).
doi:10.1016/j.canlet.2005.11.009

331. W. G. Tong, W. G. Wierda, E. Lin, S. Q. Kuang, B. N. Bekele, Z. Estrov, Y. Wei, H. Yang, M. J. Keating, G. Garcia-Manero: Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact. Epigenetics 5 (2010).
PMid:20953699

332. V. B. Chachadi, H. Cheng, D. Klinkebiel, J. K. Christman, P. W. Cheng: 5-Aza-2'-deoxycytidine increases sialyl Lewis X on MUC1 by stimulating b-galactoside:a2,3-sialyltransferase 6 gene. Int J Biochem Cell Biol (2010).

333. K. Moriwaki, M. Narisada, T. Imai, S. Shinzaki, E. Miyoshi: The effect of epigenetic regulation of fucosylation on TRAIL-induced apoptosis. Glycoconj J 27, 649-659 (2010).
doi:10.1007/s10719-010-9310-5
PMid:19734945

334. F. V. Jacinto, E. Ballestar, M. Esteller: Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation. Oncogene 28, 4212-4224 (2009).
doi:10.1038/onc.2009.267
PMid:20713525

335. J. Si, Y. A. Boumber, J. Shu, T. Qin, S. Ahmed, R. He, J. Jelinek, J. P. Issa: Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. Cancer Res 70, 6968-6977 (2010).
doi:10.1158/0008-5472.CAN-09-4474
PMid:17965433

336. H. R. Wang, C. Y. Hsieh, Y. C. Twu, L. C. Yu: Expression of the human Sda b-1,4-N-acetylgalactosaminyltransferase II gene is dependent on the promoter methylation status. Glycobiology 18, 104-113 (2008).
doi:10.1093/glycob/cwm120
PMid:17107959

337. L. MareM. Trinchera: Comparative Analysis of Retroviral and Native Promoters Driving Expression of b1,3-Galactosyltransferase b3Gal-T5 in Human and Mouse Tissues. J Biol Chem 282, 49-57 (2007).
doi:10.1074/jbc.M606666200
PMid:19560282

338. G. LaucV. Zoldos: Epigenetic regulation of glycosylation could be a mechanism used by complex organisms to compete with microbes on an evolutionary scale. Med Hypotheses 73, 510-512 (2009).
doi:10.1016/j.mehy.2009.03.059
PMid:16556489

Key Words: Glycosylation, Glycosyltransferases, Sialyl Lewis Antigens, Thomsen-Friedenreich Antigen, Gangliosides,Selectins, Galectins, Review

Send correspondence to: Fabio Dall'Olio, Department of Experimental Pathology, Via S. Giacomo 14, 40126 Bologna, Italy, Tel: 39 051 2094727, Fax: 39 051 2094746, E-mail:fabio.dallolio@unibo.it