Abstract
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 23 1 1 Jennifer Munkley and David J. Elliott Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK Correspondence to: Jennifer Munkley, email: [email protected] Keywords: cancer, glycosylation, hallmarks, glycans, aberrant Received: January 28, 2016 Accepted: March 02, 2016 Published: March 17, 2016 AbstrAct Aberrant glycosylation plays a fundamental role in key pathological steps of tumour development and progression. Glycans have roles in cancer cell signalling, tumour cell dissociation and invasion, cell-matrix interactions, angiogenesis, metastasis and immune modulation. Aberrant glycosylation is often cited as a ‘hallmark of cancer’ but is notably absent from both the original hallmarks of cancer and from the next generation of emerging hallmarks. This review discusses how glycosylation is clearly an enabling characteristic that is causally associated with the acquisition of all the hallmark capabilities. Rather than aberrant glycosylation being itself a hallmark of cancer, another perspective is that glycans play a role in every recognised cancer hallmark. Many of the first cancer-specific antibodies identified IntroductIon were directed against oncofetal antigens expressed on embryonic and tumour cells but not in adult tissues [5]. The hallmarks of cancer were originally outlined The importance of glycosylation in cancer is further in 2000 and comprise six biological capabilities acquired emphasised by that fact that the majority of FDA-approved during the multi-step development of cancer that allow tumour markers are glycoproteins or glycan antigens [6- cancer cells to survive, proliferate and disseminate [1]. 8]. The expression of cancer associated glycans such as As cells evolve progressively to a neoplastic state they X X sialyl-Lewis (SLe ), Thomsen-nouvelle antigen (Tn), acquire a succession of these hallmarks to allow them and sialyl-Tn (sTn) antigen have been detected in virtually to become tumourigenic and ultimately malignant. The every cancer type [9]. hallmarks include: sustaining proliferative signalling, Growing evidence supports crucial roles for evading growth suppressors, resisting cell death, enabling glycosylation during all steps of tumour progression, replicative immortality, inducing angiogenesis, and and it is well established that glycans regulate tumour activating invasion and metastasis [1]. Underlying theses proliferation, invasion, metastasis and angiogenesis hallmarks are genome instability and inflammation which [10, 11]. Aberrant glycosylation is frequently cited as a contribute to multiple hallmark functions [1, 2]. In 2011, hallmark of cancer [11-15], but is notably absent from more than a decade after the publication of the original both the original hallmarks paper [1] and from the next cancer hallmarks paper, the next generation of cancer generation hallmarks [3]. The goal of this review is to hallmarks were published, and two emerging hallmarks highlight glycosylation as a mechanistic concept integral were proposed: reprogramming of energy metabolism to the recognised hallmark traits. Unique to our discussion and evading immune destruction [3]. The next generation is our focus on how glycosylation enables acquisition of of cancer hallmark traits recognised the ‘tumour all the 10 currently accepted hallmarks of cancer cells. microenvironment’, or the cellular environment in which the tumour exists, as contributing to the acquisition of hallmark traits, adding another dimension of complexity GlycosylA tIon to cancer progression [3]. Aberrant glycosylation in cancer was first described Glycosylation is the enzymatic process that produces more than 45 years ago [4], and since then it has been well glycosidic linkages of saccharides to other saccharides, documented that fundamental changes in the glycosylation lipids or proteins [11]. Glycosylation is a frequent and patterns of cell surface and secreted glycoproteins occur well known post-translational protein modification, and during malignant transformation and cancer progression. probably much more frequent than phosphorylation. The www.impactjournals.com/oncotarget 35478 Oncotarget glycome, or complete pattern of glycan modifications The extracellular matrix (ECM) imparts the in a cell or tissue, is assembled by the synchronised spatial context for the signalling events of various action of numerous glycan modifying enzymes. These cell surface growth factor receptors, and is composed enzymes include glycosyltransferases and glycosidases of a dynamic and complex array of glycoproteins, that glycosylate various complex carbohydrates such as collagens, glycosaminoglycans and proteoglycans [36]. glycoproteins, glycolipids and proteoglycans. How much a Glycosylation has been shown to facilitate integrin given protein is glycosylated depends on the presence and dependent growth factor signalling to promote cell growth frequency of glycosylation sites in the protein sequence, and survival [37, 38], and can also markedly modify the as well as the expression and activities of specific function and signalling of the multifunctional cell surface glycosylation enzymes within the cell or tissue [16]. molecule CD44 [39, 40]. Ceramide glycosylation in the The two most common mechanisms by which cell membrane can actively participate in maintaining glycans are linked to proteins are O-linked glycosylation cancer stem cells by activating c-Src signalling and and N-linked glycosylation. In O-linked glycosylation, β-catenin mediated upregulation of stem cell factors sugars are added incrementally to the hydroxyl oxygen [41]. Proteoglycans also play a role in the biogenesis and of serine, threonine residues [17]. A common type recognition of exosomes (secreted vesicles of endosomal of O-linked glycosylation is initiated via addition of origin) which are involved in cell signalling [42]. GalNAc, which can then be extended into various different structures. Other types of O-glycans include those ev AdInG Growth suppressors attached via O-mannose, and the β-N-acetylglucosamine (O-GlcNAc) [18-20]. In N-linked glycosylation In addition to inducing and maintaining positively preassembled blocks of 14 sugars are transferred co- acting growth stimulatory signals, cancer cells must translationally via the amide group of an asparagine also overcome powerful programs that negatively residue and are then further processed [21]. Addition of regulate cell proliferation, many of which depend on the O-GlcNAc (O-GlcNAcylation) occurs almost exclusively actions of tumour suppressor genes. The two canonical within the cell as an alternative to phosphorylation, while suppressors of proliferation, p53 and RB (retinoblastoma) N- and O-glycans tend to be found at the cell surface as proteins have both been documented to contain potential secreted entities, meaning that intra-cellular proteins may glycosylation sites, and their functions may be controlled be effected by O-GlcNAcylation while interactions at the by dynamic O-GlcNAc modification as well as by cell surface often involve N- glycans and O-glycans [17, phosphorylation [43-45]. O-GlcNAcylation of p53 at 20, 22]. residue Ser149 is thought to promote its tumour suppressor Alterations in glycan composition can aid in activity by inhibiting its phosphorylation on Thr155 [44, various stages of cancer progression. The mechanisms 45]. Examples of gain of function p53 mutants have been that produce altered glycan structures in cancer cells widely described [46-48], and in this context it might be remain poorly understood, but are believed to involve possible that O-GlcNAcylation induced stabilisation of changes in epigenetics, genetic mutations, misregulated gain of function mutant forms of p53 could amplify its expression of glycosyltransferase and chaperone genes, pro-oncogenic activity [45]. and mislocalisation of glycosyltransferases [23-26]. dereGulA tInG cellulAr enerGetIcs sust AInInG prolIferA tIve sIGnAllInG A key feature of cancer cells is a shift from oxidative A fundamental trait of cancer cells is their ability to phosphorylation to aerobic glycolysis [49]. Known as the maintain chronic proliferation [1]. It is well established ‘Warburg effect’, this shift in metabolism is characterised that glycan expression can play a role in maintaining by high rates of glucose and glutamine uptake to cope proliferative signalling. O-GlcNAc modification of with the increased energetic and biosynthetic needs of the proteins has been shown to regulate important cell tumour. The abundance of glucose contributes to increased proteins involved in cell cycle progression including glycolysis and increased flux through metabolic pathways the transcription factor forkhead protein M1 (FoxM1), such as the hexosamine biosynthetic pathway (HBP). cyclin D1 [27], and cMYC [28]. Increased MYC The end product of the HBP is UDP-GlcNAc which is O-GlcNAcylation can compete with phosphorylation, a critical metabolite used in O-GlcNAcylation and in stabilising MYC protein and contributing to oncogenesis both N- and O-glycosylation [50]. O-GlcNAc is elevated [28]. The degree of N-glycan branching can also modulate in various types of cancer and has itself been described the activity and signalling of growth factor receptors, as a hallmark of cancer [45, 51]. O-GlcNAcylation can and can contribute to proliferative signalling [29-32]. act as a ‘nutritional sensor’, and may provide feedback Numerous growth factor receptors including EGFR, signals that modulate metabolism in response to changing FGFR, PDGF, MET and IGFR are known to be regulated nutrient status [20, 52, 53]. Several studies have suggested by glycosylation [33-35]. that hyper-O-GlcNAcylation is linked to cancer-associated www.impactjournals.com/oncotarget 35479 Oncotarget metabolic reprogramming [54]. O-GlcNAc can modify Although to date there is no evidence linking glycans a number of glycolytic enzymes [55-57], including to telomerase activation, and glycosylation of hTERT phosphofructokinase 1 (PFK1) which catalyses the rate has so far not been reported, there is indirect evidence limiting step in glycolysis [57]. O-GlcNAcylation may linking glycosylation to telomerase activation through also play a role in metabolic reprogramming by regulating the glycosylation of the transcription factor c-MYC. transcription factors [58, 59] and c-MYC stability [28]. C-MYC is a direct mediator of telomerase activation and can directly induce hTERT gene expression [78, 79]. The c-MYC protein is known to be glycosylated [80], and resIstInG cell deA th has been shown to be stabilised by modification with O-GlcNAc [28]. Levels of O-GlcNAcylation are up- Programmed cell death by apoptosis serves as a regulated in various types of cancer [45, 51], as are some natural mechanism to prevent cancer development, and of the enzymes involved in the hexosamine biosynthesis a hallmark of cancer is the ability of malignant cells pathway [81]. Future studies will help determine to evade apoptosis [1, 60]. Glycans play a key role in whether O-GlcNAc mediated stabilisation of c-MYC can many of the processes leading to cell death, and can indirectly influence telomerase activation and contribute to control intracellular signals and extracellular processes replicative immortality. that promote the initiation, execution and resolution of apoptosis [61]. Cancer cells often use their glycosylation machinery to modify glycans on cell death receptors, ActIv AtInG Inv AsIon And met Ast AsIs enabling them to resist apoptosis [61]. Glycosylation can modulate the function of death receptors including The development of malignant tumours requires Fas (CD95) and TNFR1 (tumour necrosis factor receptor the ability of tumour cells to overcome cell-cell adhesion 1) [62, 63]. The glycosylation of death receptors and and then invade surrounding tissue. Mounting evidence their canonical ligands may critically regulate apoptosis suggests that certain glycan structures can affect tumour by disrupting ligand-receptor interactions [64, 65], cell invasiveness, including the ability to disseminate modulating the formation of signalling complexes [66], through the circulation and metastasise into distant and influencing ligand secretion from effector cells [67]. organs [9]. Cancer cells often have high levels of The apoptotic machinery can be positively or negatively sialylated glycans [82], which are often associated with regulated through interactions between glycosylated malignancy and poor prognosis in patients [83-86]. receptors and glycan binding proteins [68]. Lectins are a Increased sialylation can increase local negative charges family of carbohydrate binding proteins that specifically to physically disrupt cell-cell adhesion, and promote recognise glycans. Galectin-3 association with Fas can detachment from the tumour mass through electrostatic repress apoptotic signals [69], and increase tumour cell repulsion [87]. Consistent with this, expression of the survival [70, 71]. cancer-associated sTn-antigen reduces cell adhesion in Cellular accumulation of the glycosphingolipid prostate cancer and increases migration and invasion in GD3 contributes to mitochondrial damage and plays a breast and gastric carcinoma [88-93]. Similarly, ectopic key role in apoptosis [72]. GD3 expression is upregulated expression of the sialytransferase ST6GAL1 in breast in neoplastic cells where it regulates tumour invasion cancer cells has been shown to reduce cell adhesion and survival [73]. Although an increase in GD3 would [94]. Cancer cells characteristically express proteins with normally induce apoptosis, in glioblastomas addition of truncated O-glycan structures that are thought to be due an acetyl group to the terminal sialic acid (to produce to mutations or epigenetic silencing of the COSMC gene 9-O-acetyl GD3) makes GD3 unable to induce apoptosis, [95, 96], or to increased expression of ST6GalNAc1 [88]. thus promoting tumour survival [74]. Ceramide The immature O-glycophenotype of cancer cells has been accumulation also plays a role in programmed cell death directly linked to cancer cell growth and invasion [95]. [75]. The glucosylceramide synthase (GCS) enzyme can Glycosylation can also influence the activity glycosylate ceramide and blunt its pro-apoptotic activity and localisation of proteins involved in cell adhesion, in cancer cells [76]. including the transmembrane glycoprotein E-cadherin. Over-expression of the enzyme MGAT5 in gastric cancer cells induces E-cadherin mislocalisation from the cell enAblInG replIcA tIve Immort AlIty membrane into the cytoplasm [97, 98]. MGAT5 catalyses β1,6GlcNAc branching of N-glycans on E-cadherin, An essential property of cancer cells is to overcome which in turn leads to non-functional adherens junctions, the normal cellular senescence process resulting from the impairs cell-cell adhesion and downstream signalling, shortening of telomeres. Telomerase activation is a critical and contributes to invasion and metastasis [22, 97- step in carcinogenesis and is thought to occur in over 90% 101]. Downregulation of the enzyme MGAT3 in mouse of cancers [77]. Transcriptional reactivation of the human mammary tumours increases cell migration and metastasis telomerase reverse transcriptase (hTERT) gene is a major but genetic background may modify this effect in human mechanism of cancer-specific activation of telomerase. www.impactjournals.com/oncotarget 35480 Oncotarget breast cancer cells [22, 102, 103]. MGAT3 catalyses the and aberrant glycosylation of VEGFR can modulate addition of bisecting GlcNAc to complex N-glycans and its interaction with galectins and influence blood vessel is thought to influence interactions with galectins, and to growth [112]. Glycans also play a role in angiogenesis by regulate the function of some glycoproteins, including regulating Notch signalling [114], maintaining endothelial growth factor receptors and some adhesion molecules cell survival [115], controlling vascular permeability [22]. [116], and mediating the connection of blood and As well as reducing cell-cell adhesion and aiding lymphatic vessels [117]. Changes in cytokines, growth dissociation from the primary tumour, glycans can also factors and hypoxic conditions have been shown to alter promote the adhesion of tumour cells. The SLe antigen the endothelial glycome to facilitate binding of galectin-1 is upregulated in several types of cancer [17, 104], and and activate pro-angiogenic signalling pathways, raising can promote adhesion of tumour cells to endothelial cells the possibility that a glycosylation signature could be used through interactions with selectins, in this way mediating to distinguish blood vessels at different stages of tumour the initial steps in metastasis [11, 82]. Galectin-3 regulates progression [118]. the dynamics of N-cadherin [29], and Galectin-1 binding Heparan sulfate (HS) proteoglycans are abundantly to CD44 and CD326 can promote attachment to the ECM expressed in the developing and mature vasculature, and and endothelial cells [105]. play a pivotal role in angiogenesis by facilitating the The sialyltransferase ST6GalNAc2 has been binding of cell surface pro-angiogenic growth factors identified as a metastasis suppressor in breast cancer [119-121]. HS proteoglycans have been described as cells which is linked to patient survival [106]. Loss ‘heavy hitters in the angiogenesis arena’ [122], and can of ST6GalNAc2 was found to alter the profile of modulate angiogenesis by affecting the bioavailability and O-glycans on the cell surface and facilitate Galectin-3 interaction of heparin-binding VEGFs with VEGFRs [123, binding, leading to an increased metastatic burden 124], and by interacting with anti-angiogenic factors such [106]. Glycosylation enzymes may also play a key role as endostatin [125]. In ovarian cancer HS has been shown in mediating cancer cell passage through the blood brain to impact angiogenesis through EGF receptor signalling barrier. GALNT9 (an initiator of O-glycosylation) is and influencing the expression of angiogenic cytokines frequently epigenetically dysregulated in breast tumours [126]. that metastasise to the brain [107]. The sialyltransferase ST6GalNAc5 is normally restricted to the brain, but its Genome Inst AbIlIty & mut AtIon expression in breast cancer can specifically mediate metastasis to the brain, highlighting the role of cell-surface Acquisition of the cancer hallmarks is made possible glycosylation in organ-specific metastatic interactions in part by the development of genomic instability in cancer [108]. cells which generates random mutations and chromosomal rearrangements. The accumulation of mutations can InducInG AnGIoGenesIs be accelerated by disrupting the surveillance systems that normally monitor genomic integrity. The tumor Through inducing the process of angiogenesis, suppressor p53 has long been known to play a central development of tumour associated neovasculature role in maintaining a stable genome [127]. O-GlcNAc enables tumours to acquire nutrients and oxygen as well and O-phosphate modifications co-ordinately regulate as the ability to remove metabolic waste including carbon p53 stability and activity [44], and a role for O-GlcNAc dioxide. The development of vasculature involves growing in the regulation of DNA damage signalling or repair new endothelial cells and their assembly into tubes has been suggested [128]. ATM, a key regulator of DNA (vasculogenesis), and the sprouting (angiogenesis) of new damage repair is glycosylated, and studies have indicated vessels from existing ones. In the adult the vasculature a dynamic interplay between phosphorylation and is largely quiescent, but during tumour progression an O-GlcNAc in the regulation of the DNA damage pathway ‘angiogenic switch’ is activated causing vasculature to which could be linked to genomic instability in cancer continually sprout new vessels and aid tumour growth [129]. [109]. A distinct set of glycosylation related genes has been linked to the angiogenesis process [110, 111], and it tumour promotInG InflAmmA tIon has become increasingly evident that glycans are integral to different events in the angiogenesis cascade [112]. It has long been recognised that some tumours A key inducer of angiogenesis is vascular endothelial are densely infiltrated by cells of the immune system growth factor (VEGF), which signals via receptor tyrosine and thereby mirror inflammatory conditions in non- kinases (VEGFRs) and plays a pivotal role in angiogenesis neoplastic tissues [3, 130]. Historically, these immune during development and in cancer. Glycosylation of both responses were thought to reflect an attempt by the VEGF and the VEGFRs is associated with angiogenesis. immune system to eradicate the cancerous cells, but VEGF levels are upregulated by O-GlcNAcylation [113], there is now growing evidence that the response has www.impactjournals.com/oncotarget 35481 Oncotarget an unanticipated paradoxical effect to actually aid in inflammatory cytokines [138]. The transcriptional activity tumorigenesis and cancer progression. Within the tumour of NF-κB can be regulated by O-GlcNAcylation [139], microenvironment, inflammation can contribute to which is known to be upregulated in multiple cancer types multiple hallmark capabilities [2, 3], and plays a role in the [45]. Similarly, the pro-inflammatory molecule COX2 is proliferation and survival of malignant cells, angiogenesis, also regulated by glycosylation [140], and the efficiency metastasis, subversion of adaptive immunity, and of some COX2 inhibitors is thought to be dependent on response to hormones and chemotherapy [2, 131-134]. COX2 glycosylation state [141]. Interestingly, a diet Genomic instability can also be induced by inflammatory derived sialic acid called N-glycolylneuraminic acid mediators [2]. Changes in glycan composition are closely (Neu5Gc, found primarily in red meat) can be incorporated associated with inflammation [14], and suggest an intricate in human tissues. This can lead to the production of auto- relationship between glycosylation and inflammation antibodies against Neu5Gc and subsequent tumour related in cancer progression. The selectin proteins (E-, P- inflammation via induction of ‘xenosialitis’[142]. and L-Selectin) are associated with cancer metastasis As well as glycan involvement in the inflammatory [135], but also play a key role in the entry of circulating response, the inflammatory microenvironment can also lymphocytes into peripheral lymph nodes and leukocyte reciprocally mediate changes in the glycan composition emigration into inflamed tissues [14, 136]. The selectins of cells, which could contribute to tumour malignancy. bind sialylated and fucosylated glycans (such as SLe ) Pro-inflammatory cytokines can increase the expression which act as ‘endothelial zip codes’ for the homing of of glycosyltransferases involved in the biosynthesis of lymphocytes into inflammatory sites [137]. cancer-associated antigens in pancreatic and gastric cancer Emerging evidence suggests that key mediators cell lines [143, 144]. in the inflammatory response may be regulated by glycosylation. NF-κB is a well-characterised orchestrator of inflammation which induces the expression of figure 1: Glycosylation is an enabling characteristic that is causally associated with the acquisition of all the cancer hallmark capabilities. www.impactjournals.com/oncotarget 35482 Oncotarget Wellcome Trust (grant numbers WT080368MA and AvoIdInG Immune destructIon WT089225/Z/09/Z) and BBSRC (grant BB/1006923/1 and BB/J007293/1) and Breast Cancer Now (grant number Cancer immune surveillance is thought to inhibit 2014NovPR355). carcinogenesis and is an important host protection process through which transformed cells are eliminated by immune effector cells. Growing evidence suggests that conflIcts of Interest interactions between tumour specific glycans and lectins on immune cells are involved in modulating the tumour The authors declare no conflict of interest. microenvironment [145]. 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