Tumour-Associated Carbohydrates as Cancer Targets: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Mariano Rolando Gabri.

Glycans are essential players involved in the interaction between cells and the microenvironment, making them ideal targets for the development of new therapies against infections and cancer. Since they modulate membrane receptor affinities, immune recognition, protein-protein interactions, and cell signaling, among others, glycans have been shown to play a relevant role in normal and malignant cell behaviour. Therefore, the alteration of the glycophenotype derived from malignant transformation is one of the adaptive mechanisms that provides tumour cells with growth advantages over normal cells, selected in order to circumvent the control mechanisms of the tissue microenvironment and ensure tumour survival.

  • active immunotherapy
  • TACA
  • aberrant glycosylation
  • mimicry

1. Introduction

Glycans expressed in malignant cells that participate in tumour behaviour are known as tumour-associated carbohydrate antigens (TACAs). TACAs represent an opportunity for the identification of new antigens that could potentially be suitable as immunotherapy targets. Given that they are not presented by major histocompatibility complex (MHC) molecules and that they induce immune tolerance, the development of immunotherapeutic strategies against TACAs is a real challenge. However, antitumor strategies based on mimetics of TACAs have been developed and show promising results. Active immunotherapies based on TACA mimicry can currently be grouped into strategies based on the use of mimetic peptides and anti-idiotype (Id) antibodies. All these alternatives seek to stimulate the immune system against a particular TACA to further direct a specific immunological response able to attack and eliminate tumour cells.

2. TACAs as Cancer Targets

According to their structural similarities, TACAs can be classified into five groups: (1) the globo-series glycosphingolipids, including Globo-H, Stage-specific embryonic antigen-3 (SSEA-3) and Stage-specific embryonic antigen-4 (SSEA-4); (2) the gangliosides, including GD2, GD3, GM2, NeuGcGM3, and Fuc-GM1; (3) the blood groups or Lewis antigens, including Lewis X (Lex), Lewis Y (Ley), sialyl Lewis X (SLex), and sialyl Lewis A (SLea); (4) the truncated O-glycans, including Thomsennouveau (Tn), sialyl-Tn (STn), and Thomsen−Friendreich (TF); and (5) the polysialic acid.
Glycosphingolipids share the characteristic of being composed of complex glycans covalently linked to a ceramide backbone. Globo-H ceramide is thought to be the most prevalent cancer-associated glycosphingolipid since its overexpression was detected by immunohistochemistry in a wide variety of epithelial cancers such as breast, uterus, ovary, prostate, lung, liver, and colon cancers [1][2]. Considering its expression is restricted to undifferentiated embryonic stem cells and the luminal surface of glandular tissues, some publications propose Globo-H as a potential target for cancer immunotherapy [3]. SSEA-3 and SSEA-4 were originally identified as human embryonic stem cell-specific markers, but subsequent research demonstrated their association with malignant behaviour in tumour cells [4]. The SSEA-4 expression is positively related to breast [5], glioblastoma [6], and prostate [7] cancer aggressiveness. Since its expression is related to the loss of cell-to-cell interaction and the cell migratory phenotype, SSEA-4 has been associated with epithelial-mesenchymal transition [8]. In breast cancer samples, a high percentage of positivity was reported for SSEA-3 (77.5%), which may correlate with tumorigenicity and multidrug resistance [9][10]. Similarly, in non-small cell lung cancer (NSCLC), SSEA-3 expression increases in samples resistant to multiple anticancer drugs [11]. Moreover, SSEA-3 was postulated as a novel cell surface marker in human colorectal cancer since the SSEA-3-expressing cell subpopulation has a greater proliferative capacity in vitro and a higher tumorigenicity in vivo than SSEA-3-negative cells [12].
Gangliosides are the second TACA group with a glycosphingolipid nature that are composed of at least one sialic acid in the carbohydrate structure [13][14]. The disialylganglioside GD2 is only expressed in a few normal tissues, like the brain, peripheral sensory nerve fibres, and in particular melanocytes from the skin. Nonetheless, this ganglioside is overexpressed in neuroblastomas, melanomas, retinoblastomas, and breast cancer [15][16][17][18]. It was established that GD2 is the most important complex ganglioside present in neuroblastoma, whose expression correlates with tumour progression and poor patient outcomes [19][20]. Another ganglioside widely described in association with malignant transformation is GD3, which is expressed normally in embryonic cells and in some tissues under disease conditions, such as the nervous system in neurodegenerative disorders and tumours of neuroectodermal origin [21]. Interestingly, this TACA is detected in 60% of primary melanoma and 75% of metastatic melanoma, even though it is not expressed in normal melanocytes [22]. In this indication, the upregulation of GD3 on the cell surface is associated with tumour progression, brain metastasis, and poor clinical outcome [23]. GM3 is a monosialoganglioside that can contain a N-acetylneuraminic acid (NeuAc), which is abundant in normal tissues, or a N-glycolylneuraminic acid (NeuGc), which is considered a ‘non-human’ sialic acid due to a mutation in the gene that encodes the enzyme capable of catalysing the conversion of NeuAc to NeuGc [24]. Whereas NeuGcGM3 is rarely detected in normal tissue, it is found in multiple types of tumours such as melanoma [25], neuroblastoma [26], retinoblastoma [27], colon [28], bladder [29] and lung cancer [30], among others. Most literature ascribes the presence of this sialic acid in malignant cells to the metabolic assimilation of NeuGc, obtained principally from red meat, under hypoxic conditions [31][32][33]. On the other side, Fuc-GM1 is a fucose-containing glycolipid that is naturally expressed in a subset of peripheral sensory neurons and dorsal root ganglia [34][35]. However, multiple reports have demonstrated enhanced levels of this antigen in small cell lung cancer (SCLC), even though only 20% and 10% of squamous epithelial and large cell lung cancer specimens were positive, respectively. In addition, no Fuc-GM1 was detected in lung adenocarcinoma, bronchial carcinoma, or normal lung or bronchus, so it could be considered a hallmark of SCLC and useful for sample stratification as well as for targeted immunotherapies [36][37].
Lewis antigens correspond to a family of terminal glycan structures characterised by the presence of one or two fucoses linked to a disaccharide of N-acetylglucosamine and galactose that can also be sialylated. Lex antigen, also known as Stage-Specific Embryonic Antigen-1 (SSEA-1) or CD15, is mainly found in epithelial tissues like the stomach, colon, salivary glands, kidneys, bladder, uterus, cervix, and medulla [38]. Nevertheless, the overexpression of Lex can be found on the surface of various types of cancer cells, which usually correlates with tumour progression and patient survival [39]. In bladder, hepatic, and breast cancer, this molecule is strongly associated with systemic dissemination, possibly related to its role in the adhesion of cancer cells to blood vessel walls [40][41][42]. Particularly in glioblastoma multiforme, this epitope has been proposed as a cancer stem cell marker, and it could be a potential marker of malignant glioma progression [43][44]. Its sialylated version, the terminal glycan SLex, is usually detected on the surface of lymphocytes, neutrophils, and a subset of T lymphocytes [45]. However, expression of this well-known sialofucosylated motif was also reported in high-grade gliomas [46] and gastrointestinal cancers [47]. SLex binds to selectins, mainly E-selectin, expressed on the surface of endothelial cells, facilitating leukocyte extravasation and inflammatory processes [48]. In accordance, in vivo studies have shown that Slex-positive tumour cells exhibit increased metastatic potential by arresting tumour cells in the vasculature of target organs through adhesive interactions [49][50][51]. Another member of this family is SLea, also called cancer antigen 19-9 (CA19-9), which is the most widely used and best validated marker for pancreatic cancers. It is also present in other malignancies such as gastric, endometrial, and colorectal cancers. Initially found in glycolipids, SLea is now known to also be present on glycoproteins and proteoglycans [52]. Although to date it could be considered an indicator for predicting patient prognosis, further studies are needed to fully understand its involvement in cancer biology [53][54][55]. The last TACA of this family, Ley antigen, is a prognostic factor associated with cell dedifferentiation and proliferation in NSCLC and hepatocellular carcinoma [56][57]. It has been demonstrated that the in vitro blockade of Ley significantly reduced the invasion and metastasis of ovarian cancer cells [58]. In addition, numerous publications have shown that overexpression of Ley on these tumour cells is associated with chemotherapy resistance [59][60][61].
Altered O-glycan expression is observed in several tumour indications [62][63][64]. Truncated glycans refer to a set of molecules composed of a small number of carbohydrates present as a consequence of related O-glycan core expression. In this regard, Tn and STn antigens show little or no expression in normal adult cells and tissues. Many studies have shown that Tn antigen is detected in various human carcinomas, such as those of the cervix, ovary, breast, bladder, prostate, gastric, and colon [65][66][67]. Indeed, in many cases, its expression has been associated with tumour progression, dissemination, and patient prognosis [68][69][70]. Tn and STn are frequently co-expressed in tumour cells, possibly because they share synthetic pathways. STn detection is observed in more than 80% of human carcinomas, including gastric, endometrial, and bladder tumours, and in all cases, STn expression is associated with an adverse outcome and decreased overall survival for the patients [71][72][73][74]. Although the mechanism by which STn participates in the interaction between tumour cells and the microenvironment is not fully understood, it has been reported to promote the separation of individual cells from the primary tumour mass by disrupting the interaction of galectins with terminal galactose residues. In this scenario, STn antigen could promote the escape of cancer cells participating in the migration and invasion of the surrounding tissue [75]. TF is a truncated O-glycan highly expressed in approximately 70–90% of carcinomas like ovarian, prostate, breast, colon, stomach, and bladder malignant tissues, although the percentage of positive cases varies among the carcinoma types [76]. Aberrant expression of TF antigen is usually related to the dissipation of the pH gradient in the Golgi apparatus of tumour cells, which can relocate certain glycosyltransferases, leading to an abnormal synthesis of mucin-type O-glycans [77][78]. This TACA plays a crucial role in the interaction between cancer cells and galectin-3, a carbohydrate-binding protein of the endothelium, promoting tumour aggressiveness and metastasis [79][80][81].
Tumours are not only characterised by having a high expression of monosialylated structures such as SSEA-4 or Slex, among others, but also of polysialylated glycans. These TACAs present a limited expression in normal tissue and are associated with particular proteins and cell types, especially those linked to neuronal cells. However, in clinical samples from patients with NSCLC, breast cancer, and glioblastoma, it was shown that the expression of polysialic acids and the glycosyltransferase responsible for its synthesis correlate with cell migration, invasion, and poor prognosis [12][82].
TACAs are promising targets for the development of novel therapeutic strategies due to their active participation in tumour biology (Table 1). Successful development of active immunotherapeutic approaches requires an understanding of how glycans interact with the immune system and the identification of strategies to trigger appropriate immune responses against them.
Table 1.
Main tumour-associated carbohydrate antigens (TACAs).
Name Structure Classification of Glycan Type of Cancer
Globo H Fucα1-2Galβ1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ Globo Series Breast, Uterus, Ovary, Prostate, Lung, Liver, Colon
SSEA-3 Galβ1-3GalNAcβ1-3Galα1-4Galβ1 Globo Series Breast, NSCLC, Colon
SSEA-4 Neu5Acα1-3Galβ1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ Globo Series Breast, Glioblastoma, Prostate
GD2 GalNAcβ1,4(Neu5Acα2,

8Neu5Acα2,3)Galβ1, 4Glcβ1Cer		 Gangliosides Neuroblastoma, Melanoma, Retinoblastoma, Breast
GD3 Neu5Acα2,8Neu5Acα2,3Galβ1, 4Glcβ1Cer Gangliosides Neuroectodermal, Melanoma
NeuGcGM3 Neu5Gcα2-3Galβ1-4GlcβCer Gangliosides Melanoma, Neuroblastoma, Retinoblastoma, Colon, Bladder, NSCLC
Fuc-GM1 Fucα1-2Galβ1-3GalNAcβ1-4(Neu5Acα2-3)Galβ1-4GlcβCer Gangliosides SCLC
Lex Galβ1-4(Fucα1-3)GlcNAc- Lewis antigens Bladder, Hepatic, Breast, Glioblastoma
SLex Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc Lewis antigens Glioma, Gastrointestinal
SLea Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc Lewis antigens Pancreatic, Gastric, Endometrial, Colon
Ley Fucα1-2Galβ1-4(Fucα1-3)GlcNAc- Lewis antigens NSCLC, Hepatocellular, Ovarian
Tn GalNAcαSer/Thr O-glycans Cervix, Ovarian, Breast, Prostate, Colon
STn Neu5Acα2-6GalNAcαSer/Thr O-glycans Gastric, Endometrial, Bladder
TF Galβ1-3GalNAcαSer/Thr O-glycans Ovarian, Prostate, Breast, Colon, Stomach and Bladder
Polysialic acid α2,8-/α2,9 NeuAc Polysialylated NSCLC, Breast, Glioblastoma

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