Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis

Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis Joana G. Rodriguesa,b, Meritxell Balmañaa,b, Joana A. Macedoa,b, Juliana Poçasa,b, Ângela Fernandesa,b, Julio Cesar M. de-Freitas-Juniorc, Salomé S. Pinhoa,b,d, Joana Gomesa,b, Ana Magalhãesa,b, Catarina Gomesa,b, Stefan Mereitera,b, Celso A. Reisa,b,de* a I3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. b Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal. c Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil. d Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. e Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal. Originally published in Cell Immunol. 2018 Mar 20. pii: S0008-8749(18)30121-7. DOI: 10.1016/j.cellimm.2018.03.007 ABSTRACT Tumour metastasis is the main cause of cancer related deaths. Metastasis is an intricate multi-step process that requires the acquisition of several cancer cell features, including the modulation of tumour cell migration, adhesion, invasion, and immune evasion. Changes in the cellular glycosylation are associated with malignant transformation of cancer cells, tumour progression and ultimately, metastasis formation. Glycans have major impact on cellular signalling and on the regulation of tumour cell-cell adhesion and cell-matrix interaction. Glycans drive the interplay between the cancer cells and the tumour microenvironment. In this review, we summarize the roles of glycan alterations in tumour progression, such as acquisition of oncogenic features due to modulation of receptor tyrosine kinases, proteoglycans, cadherins and integrins. We also highlight the importance of key glycan binding proteins such as selectins, siglecs and galectins, which are pivotal in the modulation of immune response. An overview on glycans as cancer biomarkers is also presented. Keywords: Glycosylation in Cancer; Biomarkers; Receptor Tyrosine Kinase; Cadherins; Integrins; Proteoglycans, Selectins; Galectins; Siglecs; Metastasis. Abbreviations: AFP-L3, α1,6-fucosylated α-fetoprotein; BPH, benign prostatic hyperplasia; CEA, carcinoembryonic antigen; CS, chondroitin sulphate; CRD, carbohydrate recognition domains; CTC, circulating tumour cell; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition; EV, extracellular vesicle; FAK, focal adhesion kinase; GAG, glycosaminoglycan; GalNAc, Nacetylgalactosamine; GlcNAc, N-acetylglucosamine; GnT, N-acetylglucosaminyltransferase; GPC, glypican; HS, heparin sulphate; HSPG, heparan sulphate proteoglycan; ITGB1, integrin β-1; NCAM, Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 neuronal cell adhesion molecule; NK, natural killer; PG, proteoglycan; PSA, prostate specific antigen; RTK, receptor tyrosine kinase; SDC, syndecan; SLea, sialyl Lewis A; SLex, Sialyl Lewis X; STn, sialyl Tn; TGM, tissue transglutaminase; TMTC, transmembrane and tetratricopeptide repeat-containing protein. 1. GLYCANS IN CANCER Glycosylation is one of the most frequent protein and lipid modification, playing an essential role in the normal development and physiology of cells [1]. Through the tight regulation and dynamic action of a variety of enzymes, namely glycosyltransferases and glycosidases, glycosylation is able to produce a wide range of glycan structures, which can exist free or conjugated to proteins or lipids [1–3]. In this review, we address the role of altered protein N-glycosylation, O-glycosylation, glycosaminoglycans (GAGs) and glycolipids, and the impact on their carrying glycoconjugates as well as the function of key glycan binding proteins in cancer metastasis. In glycoproteins, the linkage of the glycan chains to their polypeptide backbone typically occurs via nitrogen of asparagine (N-glycans) or oxygen of serine or threonine (O-glycans). N-glycans are oligosaccharides covalently linked to an asparagine at the peptide sequence Asn-X-Ser/Thr (where X represents any amino acid except proline). N-glycans share a common pentasacharide core region and can be divided in three main types: high-mannose, hybrid or complex. O-glycans are often densely clustered on serine and threonine rich protein domains, as it is the case in mucins. Glycosaminoglycans (GAGs) are large chains of linear repeating disaccharide units which can be either linked to proteoglycans or appear as free saccharides, such as hyaluronan [1–4]. Most glycans and glycoconjugates can be found in the outer surface of the cellular membrane, creating a dense coat of sugars surrounding the cells, the glycocalix. Given their position, it is not surprising that glycans play a major role in recognition and interaction processes between cells and their extracellular environment, mediating cell adhesion, cell-matrix interactions, cellular signalling, as well as hostpathogen interactions [1,3,5]. Altered expression of glycans and glycoconjugates has been associated with numerous pathologies, including congenital disorders [6], immunodeficiencies and cancer [3,4,7]. Several mechanisms have been described underlying changes in both Nand O-glycan structures. Aberrant glycosylation is the result of alterations in the cellular and molecular machinery. These include altered glyco-related gene expression, glyco-enzyme localization in the Golgi apparatus and availability of acceptor and donor substrates. Glycan alterations lead to impaired cell-cell adhesion, activation of oncogenic signalling pathways and induction of pro-metastatic phenotypes [3,8,9]. A metastatic tumour cell has to overcome cell-cell adhesion in order to detach from the primary tumour cells, migrate and invade the surrounding tissue, enter blood or lymphatic vessels, disseminate throughout the body and finally endure extravasation to metastasize into different organs. Cadherins are one of the major families of cell adhesion molecules known to be regulated by glycan structures with impact in cancer progression [9–11]. Similarly, integrins glycosylation changes are crucial to assist cancer cell invasion [3,9]. In Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 addition, specific glycan alterations have also been identified as a key players in the oncogenic activation of receptor tyrosine kinases (RTKs) [12–14]. Malignant tumour cells are known to express different subsets of glycan epitopes, including truncated simple O-glycans, changes in N-glycan branching, increased sialylation, fucosylation, and altered GAG [2,3]. Aberrant terminal sialylated glycoforms frequently modulate the interaction with carbohydrate binding proteins. Selectins and their ligands, for instance, mediate a highly regulated system of cell adhesion between leukocytes and vascular endothelial cells, an important process during inflammation [5,15], which is mimicked by the tumour cells in the metastization process. Moreover, glycans are also involved in the modulation of the immune response with glycan binding proteins, such as siglecs and galectins, regulating key immune cell functions [3,5,16,17]. Furthermore, the glycosylation alterations present in malignant tumour cells and their implication in different steps of tumour progression have major applications as biomarkers for patient diagnosis and prognosis (Figure 1) [2,3,7,18,19]. In this review, we will discuss different mechanisms through which glycosylation has been shown to regulate cancer progression steps leading to metastasis. 2. GLYCOSYLATION MODULATION OF RECEPTOR TYROSINE KINASE ACTIVITY IN CANCER Receptor tyrosine kinases (RTKs) are glycosylated transmembrane cell surface receptors that regulate cellular signalling processes, often in response to paracrine or endocrine stimuli. These include cell division, differentiation, migration and angiogenesis, which are key processes in malignant transformation and cancer progression. As a result, RTKs are among the most consistently altered gene/protein class in cancer, often leading to the constitutive activation of the receptor and thus driving tumour cell invasion and metastasis [20]. In the past, the hyperactivation of RTKs was mainly attributed to the overexpression or mutational alterations of these receptors [20]. However, it became evident in recent years that alterations in glycosylation can cause the aberrant activation of RTKs (Figure 2A). These changes cannot be detected on gene, transcript or protein levels of the receptor and have been therefore often overlooked. Alterations in glycosylation leading to increased RTK activation can stem from two main reasons: transactivating glycoconjugates or altered glycosylation of the RTK itself. Famous examples of transactivating glycoconjugates are GAGs, which can tether RTK ligands and thus, enhance receptor activation [21–23]. Also gangliosides (sialylated glycosphingolipids) have been described as important modulators of RTK activation and signal transduction. For instance, RTKs are located in glycolipidenriched microdomains which can promote or impede their activation [24,25]. Receptors such as EGFR, FGFR, MET and IGFR have been described to be regulated by gangliosides [24–26]. In this regard, Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 monosialogangliosides appear to be negative regulators and disialogangliosides positive regulators of RTK activation [26]. Regarding aberrant glycosylation of RTKs, it has been described that RTKs that stimulate cell proliferation when activated (e.g. EGFR, FGFR, IGFR and PDGFR) have evolutionary more N-glycan sites (8–16 sites) per 100 amino acids, and longer extracellular domains, as compared to growth-arrest receptors involved in organogenesis and differentiation (e.g. TGFβR1 and TGFβR2) [12]. It has been demonstrated that N-glycosylation can function as a metabolic master regulator of cell proliferation and arrest through modulation of RTK glycosylation [12]. In addition, altered glycosylation, including changes in sialylation and fucosylation of EGFR affects its dimerization and its activation in lung cancer cells [27]. Furthermore, sialylation of EGFR has been shown to regulate the receptor activity and chemosensitivity to gefitinib in colon cancer cells [28]. The importance of N-glycosylation for RTK function is further highlighted by studies that blocked Nglycan formation in cancer cells [13,29,30]. These studies show that RTKs are particularly sensitive to the impediment of N-glycosylation, either by inhibitors or gene silencing, leading to the abrogation of RTK induced signal pathways and cell growth arrest of RTK dependent cancer cells [13,30,31]. The degree of N-glycan branching, promoted by MGAT5 and inhibited by MGAT3, dictates the response to the RTK ligands EGF, FGF, IGF and PDGF in carcinoma cells [32–37]. The proposed mechanism, particularly well-studied for EGFR, is that N-glycan branching promotes the galectin mediated retention of the receptor at the cell surface and thus, facilitates the RTK ligand dependent stimulation [12,33,35]. In addition, the sialylation status of N-glycans has been shown to be particularly important for RTK membrane retention and activation. In this regard, sialic acids linked α2-6 to N-glycans have been demonstrated to interfere with galectin-1 binding and this mechanism is of importance for VEGF signalling of endothelial cells, as the reduction of α2-6 sialic acids enables VEGF independent tumour angiogenesis in cancer [38]. In gastric carcinoma, the increase of α2-3 sialylation, commonly observed by the increased formation of sialyl Lewis epitopes, leads to a more invasive phenotype through the hyperactivation of the RTKs MET and RON [14,39]. Interestingly, the use of anti-sialyl Lewis A antibody CA19-9 was shown to be sufficient to abolish the ERBB2 hyperactivation in gastric cancer cells [29]. 3. GLYCOSYLATION OF ADHESION MOLECULES IN CANCER 3.1. Glycans and cell-cell adhesion The process of carcinogenesis, tumour progression and the consequent formation of metastasis is intimately related to the loss of cell-cell adhesion, followed by the acquisition of migratory capacity and invasion of surrounding tissues [40], a process that frequently involves the loss of epithelial characteristics and gain of mesenchymal features, known as epithelial to mesenchymal transition Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 (EMT). Alterations on the cellular profile of glycans have been described to regulate the migratory and invasive capacity of cancer cells contributing to metastasis [3]. E-cadherin is a transmembrane glycoprotein described as the main cell-cell adhesion molecule in epithelial tissues, with key roles in the EMT process [41–43]. The dysregulation of the E-cadherin function in cancer has been described to occur through different mechanisms including alterations in N-glycosylation (Figure 2B) [10,42,44]. Human E-cadherin exhibits four potential N-glycosylation sites [45] and alterations on the expression profiles of E-cadherin-linked N-glycans are associated with malignant and invasive phenotypes, as well as poor survival in cancer patients [46,47]. The prevention of the abnormal N-glycosylation of E-cadherin at Asn-554 was associated with a protective effect [48,49]. N-glycosylation is also crucial for the stability of N-cadherin in glioma cells and plays a role abrogating cell-cell adhesion and promoting tumour cell migration [50]. Tumour cells often exhibit an increased activity of N-acetylglucosaminyltransferase V (GnT-V), which is encoded by the human MGAT5 gene [47,51,52]. The addition of GnT-V-mediated β1,6GlcNAc-branched N-glycans on E-cadherin is able to induce alterations on its cellular localization, from the cell membrane to the cytoplasm, impairing its biological functions [47,53] and favouring a more invasive and metastatic phenotype [18,54]. On the contrary, the modification of E-cadherin with bisecting N-acetylglucosamine (GlcNAc) N-glycans catalyzed by N-acetylglucosaminyltransferase III (GnT-III) was demonstrated to impose opposite effects on E-cadherin functions through competition with the GnT-V enzyme [53,55]. This bisecting N-linked glycans on E-cadherin was described to increase the stability of adherens junctions, leading to tumour suppression [11,47,53]. Moreover, a study with breast cancer cells lacking E-cadherin expression showed that the addition of exogenous Ecadherin culminated on the inhibition of insulin receptor signalling pathway. Besides, the stimulation of these cancer cells with insulin or insulin-like growth factor 1 led to a decrease of bisecting GlcNAc Nglycans on E-cadherin together with its cellular mislocalization and increased tumour cell invasion [36,37]. There is yet another level of regulation of E-cadherin functionality by O-mannosylation, a process that is canonically catalyzed by the O-mannosyltransferases 1 and 2 [56], with new evidences for the contribution of a homologous family of putative O-Man glycosyltransferases encoded by the four transmembrane and tetratricopeptide repeat-containing protein genes (TMTC1–4) [57]. Omannosylation is generally characterized by the attachment of mannose residues to serine or threonine amino acids [58–60]. Functional E-cadherin displays high levels of O-mannosylated glycans whereas the non-functional E-cadherin exhibits an altered pattern of protein glycosylation, namely increased β1,6GlcNAc-branched N-glycans and decreased O-mannosylation glycans that contributes to cancer progression [61]. Sialylation is also crucial for the regulation of cell adhesion process. Increased expression of sialylated glycans contributes to cell spread from the tumour mass, possibly by electrostatic repulsion, with consequent surrounding tissues invasion [62,63]. In breast cancer cells, the expression of ST6GAL1 led Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 to a reduction of cell-cell adhesion and an enhanced invasion capacity [64]. In gastric cancer, aberrant expression of sialyl-Tn (STn) was described to regulate the tumour aggressive phenotype through a negative impact on cell-cell adhesion with consequent tumour cell migration and invasion [65,66]. In accordance with this, functional alterations on the C1GALT1-specific chaperone 1 (C1GALT1C1), caused by somatic mutations and hypermethylation of the C1GALT1C1 gene, promoted the overexpression of premature truncated glycans such as STn, leading to the impairment of cell adhesion, associated with invasion and metastasis [67]. Furthermore, silencing of ST6GALNAC1, enzyme responsible for the synthesis of STn [66], culminates on a decrease of metastatic capacity of gastric cancer cells [68]. At clinical level, cancer patients that present increased sialylation are frequently associated with venous invasion and poor survival rates [66,69,70]. In addition, polysialic acid, commonly expressed in NCAM (neuronal cell adhesion molecule), is implicated in tumour development and metastasis [71,72]. 3.2. Glycans and cell-matrix interactions The extracellular matrix (ECM) is the non-cellular portion of a tissue comprised of a complex network of collagens, glycoproteins, proteoglycans and GAGs. The integrin family encompasses the major surface receptors involved in the adhesion of cells to the ECM elements. Changes in dynamics of cellECM interactions, including those orchestrated by glycans, are crucial for the acquisition of migratory and invasive behaviour during carcinoma progression [73]. Particularly N-linked glycans modulate integrin function regulating the migration capacity of tumour cells [74]. Similar to E-cadherin, the branched and bisected N-glycans affect integrin functions in an opposite manner. In gastric cancer cells, the overexpression of MGAT5 significantly enhanced the expression of β1,6GlcNAc-branched glycans on integrin α3β1 leading to increased tumour cell migration on the laminin 5 substrate; whereas the overexpression of GnT-III led to the opposite effect [75]. The expression of branched versus bisected N-glycans on the integrins also modulates its signalling activity [76]. The overexpression of GnT-III in HeLa S3 cells led not only to a suppression of the integrin α5β1-mediated cell migration but also to decreased levels of focal adhesion kinase (FAK) phosphorylation [77]. Moreover, specific N-glycosylation sites on integrins have been shown to regulate different cellular functions, such as RTK activation [78,79]. Interestingly, it has been demonstrated that the levels of GnT-V are controlled by the RAS oncogene [80]. Since integrin-linked N-glycans modulate the signalling activity, which in turn affects the branched/bisected N-glycan balance, we might speculate about the possible existence of a reciprocal regulatory mechanism. Fucosylation and sialylation are also implicated in the modulation of integrin functions. In HepG2 liver cancer cells, the inhibition of fucosylation suppressed migration as well as integrin β1-related intracellular signalling through FAK [81]. Moreover, the overexpression of ST3GAL3 in pancreatic adenocarcinoma cells promoted high levels of Sialyl Lewis X (SLex) and lower levels of α2,6-sialic acid Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 content on the α2β1 integrin-linked N-glycans, leading to enhanced FAK phosphorylation and increased invasive phenotype [82]. Interestingly, increased α2,6-sialylation promoted integrin α5β1dependent hepatocellular carcinoma cell adhesion in a mouse cell line [83]. 4. PROTEOGLYCANS AND GLYCOSAMINOGLYCANS INVOLVED IN CANCER GAGs comprise a major class of oligosaccharide structures in the ECM [84–87]. GAGs are long unbranched polysaccharides of high molecular weight. They consist of repeating disaccharide units, composed of either GlcNAc or N-acetylgalactosamine (GalNAc) and either uronic acid or galactose. GAGs are ubiquitous in mammals and have an important role in the regulation of cellular behaviour and function by interacting with other ECM components like plasma proteins, growth factors, cytokines or amino acids. GAGs are divided in five major categories: hyaluronan, chondroitin sulphate (CS), dermatan sulphate, heparin and heparan sulphate (HS) and keratan sulphate [85–88]. Proteoglycans are a family of structural and functional biomolecules ubiquitously present in ECM and cell surface playing key roles in ECM structural organization and cell signalling, contributing to the control of numerous physiological and pathological processes [89]. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Proteoglycans consist of a core protein onto which one or more GAGs are covalently attached [90,91]. According to location, proteoglycans are classified in intracellular, cell surface and extracellular proteoglycans [91]. 4.1. Intracellular Proteoglycans Serglycin is the only true intracellular proteoglycan discovered so far [92]. However, serglycin can also be found as an extracellular proteoglycan. The intracellular form mediates granulopoiesis and is involved in the retention and secretion of molecules, such as proteases, cytokines and chemokines by inflammatory cells. The extracellular serglycin plays an important role in cell-cell interactions and contributes to extravasation, colonization and growth of metastatic cells [93]. Increased expression of serglycin is associated with poor prognosis in mammary and nasopharyngeal carcinomas [94,95]. Genetic ablation of serglycin prevents lung metastasis in breast cancer mouse models [94]. The increased expression of this proteoglycan in nasopharyngeal carcinoma cells led to enhanced cancer cell motility, invasion and metastasis [95]. 4.2. Cell Surface Proteoglycans Two major families of membrane-associated proteoglycans are syndecans and glypicans. In mammals, syndecan (SDC) is a family of four distinct members (SDC1-4) which are predominantly modified with HS chains and thus belong to the heparan sulphate proteoglycans (HSPGs) [89]. The HSPGs can signal Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 and regulate important cell processes, such as adhesion, migration, proliferation and differentiation. HSPGs, due to its ability to fine-tune molecular interactions, are highly relevant to tumour progression [96]. In addition, it has become apparent that the enzymes that regulate glycan modification of HSPGs are also powerful regulators of tumour behaviour [97]. The HSPGs act cooperatively with integrins to mediate adhesion of cells to the ECM and focal adhesions formation. Disruption of cancer cell focal adhesions dictates cell migration and invasion capacity. The key role of HSPGs in metastasis formation was demonstrated by altered expression of HSPGs in breast cancer [98]. In addition, many preclinical studies and clinical trials support the investigation of anti-metastasis agents targeting HSPGs [99]. The loss of expression of SDC1 is a characteristic feature of human hepatocellular carcinomas with high metastatic potential [100]. On the other hand, SDC1 expression was associated with development, differentiation and clinical stage in colorectal cancer but not in metastasis [101]. The overexpression of SDC1 may modulate the biosynthesis and sulfation of HS affecting the expression of other proteoglycans. At transcript level, the overexpression of SDC1 has been proven to affect genes involved in growth regulation and EMT of tumour cells [102]. SDC2 overexpression enhanced the SDC1-mediated malignancy of mesenchymal tumour cells [103]. The upregulation of SDC2 is associated with development of colon cancer, and affects the cancer activity regulation in invasive capacity in lung and colon cancer cells [104,105]. The reduction of SDC2 levels induces apoptosis and may abolish growth and metastasis in breast tumour [106]. In turn, SDC3 is frequently expressed in pancreatic cancer and contributes to a poor prognosis [107]. The loss of expression of SDC4, which is ubiquitously expressed, is related to increased metastatic potential, vascular/lymphatic invasion and disease stage in non-seminomatous germ cell tumours [108]. SDC4 overexpression contributed to the development and metastasis formation of renal cell carcinoma [109] as well as to a more aggressive clinical behaviour of osteosarcomas [110]. The glypican (GPC) family consists of six members of HSPGs anchored to the external surface of the cell membrane via a GPI (glycosylphosphatidylinositol) [111,112]. In recent years the importance of GPCs in the tumorigenic process has become evident. In this regards, GPC2 and GPC3 are associated with poor prognosis in neuroblastomas and hepatocellular carcinomas, respectively [113,114], whereas GPC5 has been reported as a tumour suppressor in prostate, lung and breast cancers [115–117]. Neuron glia antigen-2/ Chondroitin Sulphate Proteoglycan 4 (NG2/CSPG4) is an integral membrane proteoglycan located on the surface of many cell types. It is a prominent component of activated pericytes and plays important functions in pericyte recruitment and vascular morphogenesis [118–120]. NG2/CSPG4 upregulation is a poor prognostic marker for hepatocellular carcinoma, head and neck patients [121,122]. 4.3. Extracellular Proteoglycans Extracellular proteoglycans, such as versican and perlecan, are important components of the ECM. Versican is a large CS proteoglycan and has the ability to modulate tumour progression in different Version: Postprint (identical content as published paper) This is a self-archived document from i3S – Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 carcinomas including breast, gastric, renal, ovarian clear cell carcinoma and osteosarcoma [123–127]. Using mouse models that spontaneously develop breast cancer, it was demonstrated that myeloid progenitor cells in the lung pre-metastatic niche express versican and the knockdown of this ECM component in the bone marrow impaired lung metastasis [128]. Perlecan is a HSPG found at tissue borders and it is described to be involved in dysplastic changes of epithelial cells. The accumulation of perlecan within the cell and the intercellular space serves as a reservoir for various growth factors helping in tumour progression, angiogenesis and metastasis in prostate tumour, laryngeal and oral squamous cell carcinomas [129–132]. Alterations affecting the amount or composition of glycans present in the ECM can trigger phenotypic changes favouring the development of tumours. The excessive hyaluronan production by murine breast cancer cells led to the expansion of cancer stem cells and the development of aggressive carcinomas [133]. On the other hand, the enhanced degradation of the ECM by overproduction of hyaluronidase 1 in human prostate carcinoma cells led to an increase of motility and proliferation, allowing also the invasion of the basement membrane and the clearing of the ECM on the metastatic site [134,135]. ECM changes are also implicated in the formation of pre-metastatic niches [136]. 5. SELECTINS IN METASTASIS A mechanism by which aberrant glycosylation enhances metastatic properties in cancer cells is by the expression of selectin ligands at the cell surface, such as SLex. Selectins are a family of multifunctional adhesion glycoproteins that bind to carbohydrates in a calcium-dependent manner. They are type I membrane proteins that consist of an N-terminal lectin domain, an EGF-like module, followed by 2-9 consensus repeats, a transmembrane region and a short cytoplasmic tail [137,138]. There are three members of the selectin family: E-, Land P-selectin that differ in the number of the consensus repeats, their cell type dependent expression patterns and the biological functions. E-selectin is expressed exclusively on the activated endothelium, L-selectin is predominantly expressed on leucocytes and Pselectin on activated platelets and endothelial cells [139]. Selectins are key players in physiological and disease-related processes such as inflammation, by mediating the adhesion of leucocytes and platelets with the endothelium in the bloodstream. Nevertheless, selectins and their ligands are not only involved in processes such as leukocyte homing but also cancer [140]. During inflammation, and upon cytokine stimuli, E-selectin is expressed on endothelial cells promoting the rolling, arrest and transmigration of leucocytes. This process is mediated by the interaction of selectins with SLex and SLea containing glycoproteins and glycolipids on leucocytes. A similar process has been claimed in cancer cells. Interactions of cancer cells with selectins have been well documented in various cancer types and associated with an enhanced metastatic capacity [141–143]. In addition, Pselectin cancer cell interaction is described to promote the formation of platelet-cancer cell microemboli being associated to tumour metastasis [144]. 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