Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?

This review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we discuss the future challenges of the field, outlining potential applications of glycan-based biomarkers for patient stratification and strategies for improving personalized cancer treatment. This review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we discuss the future challenges of the field, outlining potential applications of glycan-based biomarkers for patient stratification and strategies for improving personalized cancer treatment. Carbohydrate chains, known as glycans, are key components of biological systems underlying a variety of essential structural and functional roles across all living organisms (Varki et al., 2015Varki A. Cummings R.D. Esko J.D. Stanley P. Hart G.W. Aebi M. Darvill A.G. Kinoshita T. Packer N.H. Prestegard J.H. Essentials of Glycobiology. Cold Spring Harbor Laboratory Press, 2015Google Scholar). Glycans control and define fundamental molecular, cellular, tissue, organ, and systemic biological processes directing crucial physiological functions and, therefore, being involved in a myriad of human diseases, including cancer (Pinho and Reis, 2015Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat. Rev. Cancer. 2015; 15: 540-555Crossref PubMed Scopus (1594) Google Scholar). The cellular glycome is composed of different sets of macromolecules containing covalently linked glycans, known as glycoconjugates. The different classes of glycoconjugates include glycosphingolipids, proteoglycans, and glycoproteins (Figure 1A ). Proteins can be glycosylated by the covalent attachment of a saccharide to a polypeptide backbone, mainly via N-linkage to asparagine or O-linkage to serine or threonine. Protein O-linked glycans are initiated by different saccharides and in some cases restricted to specific protein domains. In addition, intracellular proteins can be modified with the O-linked N-acetylglucosamine (O-GlcNAcylation) (Pinho and Reis, 2015Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat. Rev. Cancer. 2015; 15: 540-555Crossref PubMed Scopus (1594) Google Scholar, Varki et al., 2015Varki A. Cummings R.D. Esko J.D. Stanley P. Hart G.W. Aebi M. Darvill A.G. Kinoshita T. Packer N.H. Prestegard J.H. Essentials of Glycobiology. Cold Spring Harbor Laboratory Press, 2015Google Scholar). Cellular glycosylation is a highly regulated multistep process. However, alterations in the biosynthesis of glycans occur in cancer, leading to marked changes in glycan expression, such as truncated O-glycans, branched N-glycans, diverse fucosylated and sialylated terminal structures, and alterations in glycosphingolipid expression (Figure 1B) (Pinho and Reis, 2015Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat. Rev. Cancer. 2015; 15: 540-555Crossref PubMed Scopus (1594) Google Scholar). Alterations in glycosylation can stem from a variety of mechanisms. These can include expression levels of glycosyltransferases and glycosidases (Abbott et al., 2008Abbott K.L. Nairn A.V. Hall E.M. Horton M.B. McDonald J.F. Moremen K.W. Dinulescu D.M. Pierce M. Focused glycomic analysis of the N-linked glycan biosynthetic pathway in ovarian cancer.Proteomics. 2008; 8: 3210-3220Crossref PubMed Scopus (97) Google Scholar, Bennett et al., 2012Bennett E.P. Mandel U. Clausen H. Gerken T.A. Fritz T.A. Tabak L.A. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family.Glycobiology. 2012; 22: 736-756Crossref PubMed Scopus (531) Google Scholar, Marcos et al., 2004Marcos N.T. Pinho S. Grandela C. Cruz A. Samyn-Petit B. Harduin-Lepers A. Almeida R. Silva F. Morais V. Costa J. et al.Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen.Cancer Res. 2004; 64: 7050-7057Crossref PubMed Scopus (173) Google Scholar), changes of glycosyltransferase localization within the secretory pathway (Golgi apparatus and ER) (Nguyen et al., 2017Nguyen A.T. Chia J. Ros M. Hui K.M. Saltel F. Bard F. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis.Cancer Cell. 2017; 32: 639-653.e6Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), and modified molecular chaperone activity (Wang et al., 2010Wang Y. Ju T. Ding X. Xia B. Wang W. Xia L. He M. Cummings R.D. Cosmc is an essential chaperone for correct protein O-glycosylation.Proc. Natl. Acad. Sci. U S A. 2010; 107: 9228-9233Crossref PubMed Scopus (145) Google Scholar), as well as metabolic alterations and donor substrate availability (Itkonen et al., 2013Itkonen H.M. Minner S. Guldvik I.J. Sandmann M.J. Tsourlakis M.C. Berge V. Svindland A. Schlomm T. Mills I.G. O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells.Cancer Res. 2013; 73: 5277-5287Crossref PubMed Scopus (202) Google Scholar, Lucena et al., 2016Lucena M.C. Carvalho-Cruz P. Donadio J.L. Oliveira I.A. de Queiroz R.M. Marinho-Carvalho M.M. Sola-Penna M. de Paula I.F. et al.Epithelial mesenchymal transition induces aberrant glycosylation through hexosamine biosynthetic pathway activation.J. Biol. Chem. 2016; 291: 12917-12929Crossref PubMed Scopus (74) Google Scholar). Analysis of altered glycosylation on glycoconjugates either present on the surface or secreted by cancer cells has been largely applied to the cancer biomarker field. In fact, various serological assays are based on quantifying glycoconjugates in the serum of patients with cancer, such as the CA19-9 that detects the sialyl Lewis a (SLea) tumor antigen in gastrointestinal tumors, the CA125 that detects the mucin glycoprotein MUC16 in ovarian cancer, and the fucosylated form of the α-fetoprotein used for the diagnosis and monitoring of hepatocellular carcinoma (Adamczyk et al., 2012Adamczyk B. Tharmalingam T. Rudd P.M. Glycans as cancer biomarkers.Biochim. Biophys. Acta. 2012; 1820: 1347-1353Crossref PubMed Scopus (382) Google Scholar). Functionally, glycans control or affect several aspects of cancer cell biology, ranging from cellular adhesion, extracellular matrix interactions, cellular signaling and proliferation, and proximal and distal communication. These biological processes underlie critical cancer hallmarks such as invasion, angiogenesis, and metastasis formation, along with the development of enabling cancer features including the modulation of the immune response (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Pinho and Reis, 2015Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat. Rev. Cancer. 2015; 15: 540-555Crossref PubMed Scopus (1594) Google Scholar, Rodriguez et al., 2018Rodriguez E. Schetters S.T.T. van Kooyk Y. The tumor glyco-code as a novel immune checkpoint for immunotherapy.Nat. Rev. Immunol. 2018; 18: 204-211Crossref PubMed Scopus (204) Google Scholar). Recent developments in the clinical oncology field have provided significant advances in cancer management with substantial improvements for patients' outcome and survival. However, it became clear that the innovative treatment strategies targeting specific proteins expressed by both cancer cells and immune cells, such as receptor tyrosine kinases (RTKs) or immune checkpoint molecules, are only effective in subsets of tumors and patients. This clinical outcome variation highlights the need for patient stratification and strengthens the concept of personalized medicine. Current targeted cancer therapy guidelines include the screening of genetic markers, the detection of specific protein targets by immunohistochemistry, and the detection of other biomarkers to provide the best treatment for each patient (Jameson and Longo, 2015Jameson J.L. Longo D.L. Precision medicine—personalized, problematic, and promising.N. Engl. J. Med. 2015; 372: 2229-2234Crossref PubMed Scopus (639) Google Scholar). Unfortunately, there is still a large number of patients presenting with non-responsive malignant neoplasia or who, along the treatment course, develop tumors with resistance to the therapeutic agents. Given the critical role of glycans in tumor biology, including its microenvironment and the immune response regulation, it has become evident that glycosylation alterations occurring in cancer can have a major impact on cancer therapy. Altered glycosylation can interfere with RTK functions, as well as with cell adhesion molecules such as integrins and cadherins (Pinho and Reis, 2015Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat. Rev. Cancer. 2015; 15: 540-555Crossref PubMed Scopus (1594) Google Scholar). In addition, tumor-associated glycans can bind to endogenous lectins, such as galectins, sialic acid-binding immunoglobulin-type lectins (Siglecs), and selectins (Rodriguez et al., 2018Rodriguez E. Schetters S.T.T. van Kooyk Y. The tumor glyco-code as a novel immune checkpoint for immunotherapy.Nat. Rev. Immunol. 2018; 18: 204-211Crossref PubMed Scopus (204) Google Scholar). Therefore, the amount of information enclosed in the glycome and glycoproteome in a tumor context emerges as pivotal for the understanding of the many crucial factors that affect cancer progression, tumor immunity, and patients' clinical outcome. This knowledge is expected to provide additional biomarkers for patient stratification and provide novel targets for improved and personalized cancer therapy. RTKs and their signaling cascades are critical players in cancer progression and drive multiple cellular processes, including growth, migration, proliferation, differentiation, and apoptosis. Most RTKs are canonically activated by receptor-specific ligand binding, inducing receptor dimerization and/or oligomerization. However, recent studies have shown that alterations in glycosylation can affect the conformational arrangements of their extracellular domain, causing aberrant activation and signaling, as demonstrated for epidermal growth factor receptor (EGFR) (Contessa et al., 2008Contessa J.N. Bhojani M.S. Freeze H.H. Rehemtulla A. Lawrence T.S. Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells.Cancer Res. 2008; 68: 3803-3809Crossref PubMed Scopus (146) Google Scholar, Kaszuba et al., 2015Kaszuba K. Grzybek M. Orlowski A. Danne R. Rog T. Simons K. Coskun U. Vattulainen I. N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes.Proc. Natl. Acad. Sci. U S A. 2015; 112: 4334-4339Crossref PubMed Scopus (103) Google Scholar). Changes in glycosylation, such as terminal sialylation, fucosylation, or oligosaccharide branching, have been described to affect the interaction and subsequently the activation capacity of RTKs (Contessa et al., 2008Contessa J.N. Bhojani M.S. Freeze H.H. Rehemtulla A. Lawrence T.S. Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells.Cancer Res. 2008; 68: 3803-3809Crossref PubMed Scopus (146) Google Scholar, Liu et al., 2011Liu Y.C. Yen H.Y. Chen C.Y. Chen C.H. Cheng P.F. Juan Y.H. Chen C.H. Khoo K.H. Yu C.J. Yang P.C. et al.Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells.Proc. Natl. Acad. Sci. U S A. 2011; 108: 11332-11337Crossref PubMed Scopus (285) Google Scholar) (Figure 2). For example, increased sialylation and outer arm fucosylation precludes EGFR dimerization and receptor activation in lung cancer cells, whereas increased core fucosylation promotes this process (Liu et al., 2011Liu Y.C. Yen H.Y. Chen C.Y. Chen C.H. Cheng P.F. Juan Y.H. Chen C.H. Khoo K.H. Yu C.J. Yang P.C. et al.Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells.Proc. Natl. Acad. Sci. U S A. 2011; 108: 11332-11337Crossref PubMed Scopus (285) Google Scholar). Moreover, in gastric carcinoma cells, increased α2,3-sialylation leads to the hyperactivation of the RTKs MET and RON, resulting in a more invasive phenotype (Gomes et al., 2013Gomes C. Osorio H. Pinto M.T. Campos D. Oliveira M.J. Reis C.A. Expression of ST3GAL4 leads to SLe(x) expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells.PLoS One. 2013; 8: e66737Crossref PubMed Scopus (82) Google Scholar, Mereiter et al., 2016Mereiter S. Magalhaes A. Adamczyk B. Jin C. Almeida A. Drici L. Ibanez-Vea M. Gomes C. Ferreira J.A. Afonso L.P. et al.Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer.Biochim. Biophys. Acta. 2016; 1860: 1795-1808Crossref PubMed Scopus (39) Google Scholar). These altered glycosylation changes observed in RTKs are known to allow galectin recognition and to promote receptor retention at the cancer cell surface, facilitating receptor activation (Box 1 and Figure 3) (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar). Protein O-glycosylation is also capable of modulating the activation of RTKs. This has been demonstrated by the increased EGFR and human epidermal growth factor receptor 2 (HER2) phosphorylation in pancreatic cancer cells with knockdown of N-acetylgalactosaminyltransferase III (MGAT3) expression (Chugh et al., 2016Chugh S. Meza J. Sheinin Y.M. Ponnusamy M.P. Batra S.K. Loss of N-acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation.Br. J. Cancer. 2016; 114: 1376-1386Crossref PubMed Scopus (33) Google Scholar), one of 20 enzymes known to be able to catalyze the first step in mucin-type O-glycosylation (Bennett et al., 2012Bennett E.P. Mandel U. Clausen H. Gerken T.A. Fritz T.A. Tabak L.A. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family.Glycobiology. 2012; 22: 736-756Crossref PubMed Scopus (531) Google Scholar). Moreover, it has been described that MGAT3 knockdown also leads to an increase in the tumor-associated antigens sialyl Tn (STn) and sialyl Lewis X (SLex), conferring increased aggressiveness and metastatic potential to the tumor cells (Chugh et al., 2016Chugh S. Meza J. Sheinin Y.M. Ponnusamy M.P. Batra S.K. Loss of N-acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation.Br. J. Cancer. 2016; 114: 1376-1386Crossref PubMed Scopus (33) Google Scholar). Additional mechanisms modulating the activation of RTKs have been described via the interaction with glycosaminoglycans, proteoglycans, sialylated glycosphingolipids, and other glycosylated transmembrane proteins (Julien et al., 2013Julien S. Bobowski M. Steenackers A. Le Bourhis X. Delannoy P. How do gangliosides regulate RTKs signaling?.Cells. 2013; 2: 751-767Crossref PubMed Scopus (68) Google Scholar, Shintani et al., 2006Shintani Y. Takashima S. Asano Y. Kato H. Liao Y. Yamazaki S. Tsukamoto O. Seguchi O. Yamamoto H. Fukushima T. et al.Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.EMBO J. 2006; 25: 3045-3055Crossref PubMed Scopus (131) Google Scholar). Heparan sulfate containing proteoglycans are illustrative examples of glycoconjugates that modulate the activation of RTKs. Growth factors, such as hepatocyte growth factor or vascular endothelial growth factor, are tethered to the cancer cell surface by heparan sulfate chains, facilitating ligand-mediated receptor activation and downstream signal transduction (Shintani et al., 2006Shintani Y. Takashima S. Asano Y. Kato H. Liao Y. Yamazaki S. Tsukamoto O. Seguchi O. Yamamoto H. Fukushima T. et al.Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.EMBO J. 2006; 25: 3045-3055Crossref PubMed Scopus (131) Google Scholar). Moreover, the degree of N-glycan branching of α5 integrin has been shown to positively regulate EGFR signaling and affect cell proliferation, highlighting the role of glycosylation in key cancer cell molecules (Hang et al., 2016Hang Q. Isaji T. Hou S. Zhou Y. Fukuda T. Gu J. N-Glycosylation of integrin alpha5 acts as a switch for EGFR-mediated complex formation of integrin alpha5beta1 to alpha6beta4.Sci. Rep. 2016; 6: 33507Crossref PubMed Scopus (27) Google Scholar).Box 1Families of Human Lectins with Crucial Roles in Cancer Progression and Cancer TherapyGalectinsTypeGalectin-type lectinsLigandβ-GalactosidesFamilyNine members: galectin-1 -2, -3, -4, -7, -8, -9, -10, and -12Subgroup•Prototype lectins with one glycan-binding domain (e.g., galectin-1)•Tandem-repeat galectins with two glycan-binding domains (e.g., galectin-9)•Chimera-type galectin (galectin-3) with one glycan-binding domain and the potential to form oligomersLocalizationSecreted or intracellular soluble proteinsExpressed byCancer cells and other cells of the tumor microenvironmentFunctionGalectins engage in protein-glycan and protein-protein interactions and cluster glycoproteins with specific glycosylation at the cell surface by forming galectin lattices, increasing cell surface retention, and modulating their function and activityExemplified roles in cancer•Galectin-1 induces anti-inflammatory conditions, stimulates integrin-mediated signaling cascades in cancer cells, and stimulates angiogenesis (Croci et al., 2014Croci D.O. Cerliani J.P. Dalotto-Moreno T. Mendez-Huergo S.P. Mascanfroni I.D. Dergan-Dylon S. Toscano M.A. Caramelo J.J. Garcia-Vallejo J.J. Ouyang J. et al.Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.Cell. 2014; 156: 744-758Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, Rubinstein et al., 2004Rubinstein N. Alvarez M. Zwirner N.W. Toscano M.A. Ilarregui J.M. Bravo A. Mordoh J. Fainboim L. Podhajcer O.L. Rabinovich G.A. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege.Cancer Cell. 2004; 5: 241-251Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar)•Galectin-9 engages with the immune checkpoint TIM-3 (Gleason et al., 2012Gleason M.K. Lenvik T.R. McCullar V. Felices M. O'Brien M.S. Cooley S.A. Verneris M.R. Cichocki F. Holman C.J. Panoskaltsis-Mortari A. et al.Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9.Blood. 2012; 119: 3064-3072Crossref PubMed Scopus (260) Google Scholar)•Galectin-3 forms lattices with immune receptors such as CTLA-4 and T cell receptor-modulating immune cell activation (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar)•Galectin-3 promotes RTK cell surface retention, dimerization, and activation in carcinoma cells (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Partridge et al., 2004Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. Nabi I.R. Wrana J.L. Dennis J.W. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis.Science. 2004; 306: 120-124Crossref PubMed Scopus (590) Google Scholar)SiglecsTypeImmunoglobulin-like lectinsLigandSialylated moietiesFamilyFifteen members: Siglec-1 to Siglec-16 (with the exception of -13)Subgroups•Group of highly conserved but relatively distinct Siglecs, comprising Siglec-1, -2 (CD22), -4, and -15•Siglec-3-related group, with low evolutionary conservation but high identity with other members of the groupLocalizationTransmembrane proteinsExpressed byImmune cells (except Siglec-4, -6, and -12)FunctionMost Siglecs function as antagonists of immune activation through cytoplasmic immune receptor tyrosine-based inhibition motifs, which stall signaling cascades induced by immune receptor tyrosine-based activation motifs (Crocker et al., 2007Crocker P.R. Paulson J.C. Varki A. Siglecs and their roles in the immune system.Nat. Rev. Immunol. 2007; 7: 255-266Crossref PubMed Scopus (1402) Google Scholar)Exemplified roles in cancer•Siglec-9 on tumor-infiltrating macrophages recognizes sialylated glycans on MUC1 expressed in cancer cells, leading to an inhibitory immune signaling (Beatson et al., 2016Beatson R. Tajadura-Ortega V. Achkova D. Picco G. Tsourouktsoglou T.D. Klausing S. Hillier M. Maher J. Noll T. Crocker P.R. et al.The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9.Nat. Immunol. 2016; 17: 1273-1281Crossref PubMed Scopus (186) Google Scholar, Bhatia et al., 2019Bhatia R. Gautam S.K. Cannon A. Thompson C. Hall B.R. Aithal A. Banerjee K. Jain M. Solheim J.C. Kumar S. Batra S.K. Cancer-associated mucins: role in immune modulation and metastasis.Cancer Metastasis Rev. 2019; https://doi.org/10.1007/s10555-018-09775-0Crossref PubMed Scopus (108) Google Scholar)•Siglec-7 and Siglec-9 interact with sialylated ligands on tumor cells and influence natural killer cell activation (Jandus et al., 2014Jandus C. Boligan K.F. Chijioke O. Liu H. Dahlhaus M. Demoulins T. Schneider C. Wehrli M. Hunger R.E. Baerlocher G.M. et al.Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance.J. Clin. Invest. 2014; 124: 1810-1820Crossref PubMed Scopus (246) Google Scholar)•Siglec-9, expressed by special subsets of T cells, engages with cancer cell glycans and acts as an inhibitory receptor (Haas et al., 2019Haas Q. Frias Boligan K. Jandus C. Schneider C. Simillion C. Stanczak M.A. Haubitz M. Seyed Jafari S.M. Zippelius A. Baerlocher G.M. et al.Siglec-9 regulates an effector memory CD8+ T-cell subset that congregates in the melanoma tumor microenvironment.Cancer Immunol. Res. 2019; 7: 707-718Crossref PubMed Scopus (64) Google Scholar, Stanczak et al., 2018Stanczak M.A. Siddiqui S.S. Trefny M.P. Thommen D.S. Boligan K.F. von Gunten S. Tzankov A. Tietze L. Lardinois D. Heinzelmann-Schwarz V. et al.Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells.J. Clin. Invest. 2018; 128: 4912-4923Crossref PubMed Scopus (144) Google Scholar)SelectinsTypeC-type lectinsLigandSialofucosylated glycansFamilyThree members: E-, L-, and P-selectinLocalizationTransmembrane proteins.Expressed byEndothelial cells (E- and P-selectin), leukocytes (L-selectin), and platelets (P-selectin)FunctionIn the course of inflammation, sialyl Lewis X glycan structures expressed by circulating leukocytes bind to selectins of vascular endothelial cells, initiating the process of extravasation (McEver, 2015McEver R.P. Selectins: initiators of leucocyte adhesion and signaling at the vascular wall.Cardiovasc. Res. 2015; 107: 331-339Crossref PubMed Scopus (292) Google Scholar)Exemplified roles in cancerThe aberrant expression of sialyl Lewis structures in circulating tumor cells mediates the initial steps of extravasation through endothelial interactions, ultimately increasing the metastatic potential of cancer cells. In addition, it protects from clearance through the formation of a protective platelet cloak (Esposito et al., 2019Esposito M. Mondal N. Greco T.M. Wei Y. Spadazzi C. Lin S.C. Zheng H. Cheung C. Magnani J.L. Lin S.H. et al.Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis.Nat. Cell Biol. 2019; 21: 627-639Crossref PubMed Scopus (125) Google Scholar, Kohler et al., 2010Kohler S. Ullrich S. Richter U. Schumacher U. E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung.Br. J. Cancer. 2010; 102: 602-609Crossref PubMed Scopus (119) Google Scholar, Li et al., 2013Li J. Guillebon A.D. Hsu J.W. Barthel S.R. Dimitroff C.J. Lee Y.F. King M.R. Human fucosyltransferase 6 enables prostate cancer metastasis to bone.Br. J. Cancer. 2013; 109: 3014-3022Crossref PubMed Scopus (45) Google Scholar) GalectinsTypeGalectin-type lectinsLigandβ-GalactosidesFamilyNine members: galectin-1 -2, -3, -4, -7, -8, -9, -10, and -12Subgroup•Prototype lectins with one glycan-binding domain (e.g., galectin-1)•Tandem-repeat galectins with two glycan-binding domains (e.g., galectin-9)•Chimera-type galectin (galectin-3) with one glycan-binding domain and the potential to form oligomersLocalizationSecreted or intracellular soluble proteinsExpressed byCancer cells and other cells of the tumor microenvironmentFunctionGalectins engage in protein-glycan and protein-protein interactions and cluster glycoproteins with specific glycosylation at the cell surface by forming galectin lattices, increasing cell surface retention, and modulating their function and activityExemplified roles in cancer•Galectin-1 induces anti-inflammatory conditions, stimulates integrin-mediated signaling cascades in cancer cells, and stimulates angiogenesis (Croci et al., 2014Croci D.O. Cerliani J.P. Dalotto-Moreno T. Mendez-Huergo S.P. Mascanfroni I.D. Dergan-Dylon S. Toscano M.A. Caramelo J.J. Garcia-Vallejo J.J. Ouyang J. et al.Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.Cell. 2014; 156: 744-758Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, Rubinstein et al., 2004Rubinstein N. Alvarez M. Zwirner N.W. Toscano M.A. Ilarregui J.M. Bravo A. Mordoh J. Fainboim L. Podhajcer O.L. Rabinovich G.A. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege.Cancer Cell. 2004; 5: 241-251Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar)•Galectin-9 engages with the immune checkpoint TIM-3 (Gleason et al., 2012Gleason M.K. Lenvik T.R. McCullar V. Felices M. O'Brien M.S. Cooley S.A. Verneris M.R. Cichocki F. Holman C.J. Panoskaltsis-Mortari A. et al.Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9.Blood. 2012; 119: 3064-3072Crossref PubMed Scopus (260) Google Scholar)•Galectin-3 forms lattices with immune receptors such as CTLA-4 and T cell receptor-modulating immune cell activation (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar)•Galectin-3 promotes RTK cell surface retention, dimerization, and activation in carcinoma cells (Lau et al., 2007Lau K.S. Partridge E.A. Grigorian A. Silvescu C.I. Reinhold V.N. Demetriou M. Dennis J.W. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.Cell. 2007; 129: 123-134Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, Partridge et al., 2004Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. Nabi I.R. Wrana J.L. Dennis J.W. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis.Science. 2004; 306: 120-124Crossref PubMed Scopus (590) Google Scholar)SiglecsTypeImmunoglobulin-like lectinsLigandSialylated moietiesFamilyFifteen members: Siglec-1 to Siglec-16 (with the exception of -13)Subgroups•Group of highly conserved but relatively distinct Siglecs, comprising Siglec-1, -2 (CD22), -4, and -15•Siglec-3-related group, with low evolutionary conservation but high identity with other members of the groupLocalizationTransmembrane proteinsExpressed byImmune cells (except Siglec-4, -6, and -12)FunctionMost Siglecs function as antagonists of immune activation through cytoplasmic immune receptor tyrosine-based inhibition motifs, which stall signaling cascades induced by immune receptor tyrosine-based activation motifs (Crocker et al., 2007Crocker P.R. Paulson J.C. Varki A. Siglecs and their roles in the immune system.Nat. Rev. Immunol. 2007; 7: 255-266Crossref PubMed Scopus (1402) Google Scholar)Exemplified roles in cancer•Siglec-9 on tumor-infiltrating macrophages recognizes sialylated