The Sweet and Sour of Cancer: Glycans as Novel Therapeutic Targets

Mark M. Fuster; Jeffrey D. Esko

Disclosures
In This Article

Abstract and Introduction

A growing body of evidence supports crucial roles for glycans at various pathophysiological steps of tumour progression. Glycans regulate tumour proliferation, invasion, haematogenous metastasis and angiogenesis, and increased understanding of these roles sets the stage for developing pharmaceutical agents that target these molecules. Such novel agents might be used alone or in combination with operative and/or chemoradiation strategies for treating cancer.

Several glycans, on both the tumour surface and host elements, have now been identified as mediating key pathophysiological events during the various steps of tumour progression. Tumour progression involves a range of unique alterations in intracellular and intercellular signalling. These serve to promote dysregulation of the cell cycle and facilitate proliferation; to promote the emergence of a subset of invasive cells that dissociate from the tumour and digest and migrate through host extracellular matrix (ECM) and basement membranes; to summon an endothelial-lined neovascular network from nearby host endothelial cells (angiogenesis); to endow disseminating tumour cells with cell-surface characteristics that promote adhesive interactions with platelets, leukocytes and blood or lymphatic vascular endothelial cells; and to facilitate the evasion of innate immunity. Ultimately, a 'survivor' subset of cells must invade, neovascularize, disseminate, extravasate and proliferate at a new tissue location to become a pathological metastasis.

Glycans are covalent assemblies of sugars (oligosaccharides and polysaccharides) that exist in either free form or in covalent complexes with proteins or lipids (GLYCOCONJUGATES). There are several main families of glycoconjugates: the Asn-linked (N-LINKED) oligosaccharides of many GLYCOPROTEINS; the Ser- or Thr-linked (O-LINKED) oligosaccharides that are present on many glycoproteins and that predominate on secreted and membrane bound MUCINS; the glycosaminoglycans, which are glycans present as free polysaccharides (such as hyaluronan) or as part of PROTEOGLYCANS (such as heparan sulphate and chondroitin sulphate); the glycosphingolipids, which consist of oligosaccharides glycosidically linked to ceramide; the glycosylphosphatidylinositol (GPI)-linked proteins, which are proteins that bear a glycan chain linked to phosphatidylinositol; and nuclear and cytoplasmic proteins, which bear the monosaccharide O-linked N-acetylglucosamine (O-GlcNAc) linked to serine, often at sites that are normally phosphorylated[1] (Fig. 1). Most classes of glycan exist as membrane-bound glycoconjugates (for example, in the GLYCOCALYX) or as secreted molecules, which can become integral parts of the ECM. These locations place glycans in a position to mediate cell adhesion and motility, as well as intracellular signalling events.[2]

Important glycans involved in tumour progression.Unique glycans are involved in promoting the progression of various carcinomas. a | N-linked glycans on glycoproteins are covalently bound to Asn residues. Typical branched structures contain two or more 'antennae'. The enzyme N-acetylglucosaninyltransferase V (GnTV) generates a specific antenna on some glycoproteins and has been implicated in tumour invasion. b | O-linked glycans are found covalently linked to Ser or Thr residues on glycoproteins and mucins. SLeX/A (sialyl Lewis X or A) are carbohydrate determinants composed of four sugars in specific linkage to one another, and are commonly overexpressed on tumour-cell mucins. The determinant forms part of a ligand for the selectin class of adhesion receptors involved in tumour-cell aggregation with leukocytes and platelets, and adhesion of tumour cells to endothelial cells. Tn and STn are tumour antigens that consist of truncated O-linked chains. Their accumulation in many tumours correlates with invasion. c | Glycosphingolipids consist of the lipid ceramide linked to one or more sugars. Certain sialic-acid-containing glycosphingolipids, called gangliosides (for example, GM1, GM3, GD2 and GD3), have been correlated with tumour growth. d | Glycosylphosphatidylinositol (GPI)-linked proteins are anchored in the outer leaflet of the plasma membrane by a glycan covalently linked to phosphatidylinositol. Glycosaminoglycans can occur as free chains (hyaluronan; e) or as covalent complexes with proteoglycan core proteins (heparan sulphate, chondroitin sulphate and dermatan sulphate, a type of chondroitin-sulphate-containing iduronic acid (IdoA)). f | Proteoglycans participate in growth-factor activation and cell adhesion. g | Various cytoplasmic and nuclear proteins contain O-linked N-acetylglucosamine (O-GlcNAc). Some glycoconjugates can be tethered to the plasma membrane as depicted or secreted into the extracellular matrix. In some cases, hybrid molecules exist, containing more than one type of glycan. Sugars are represented by coloured geometric symbols. Glc, glucose; Gal, galactose; Man, mannose; GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine; GlcA, glucuronic acid; Fuc, fucose; Xyl, xylose; Sia, sialic acid.

In the tumour environment, changes in glycosylation allow neoplastic cells to usurp many of the events that occur in development (for example, receptor activation, cell adhesion and cell motility), which allows tumour cells to invade and spread throughout the organism.[3] Malignant transformation is often accompanied by the expression of oncofetal antigens — epitopes that are expressed on embryonic tissues and tumour cells, and only in a few cell types in the adult. Many of the first-identified tumour-specific antibodies were directed against carbohydrate oncofetal antigens presented on tumour glycoproteins and glycosphingolipids.[3,4] In some cases, the underexpression, truncation or altered branching patterns of certain glycans correlate with cell growth. Similar alterations on tumours endow them with enhanced proliferative capacity, which could reflect the outcome of 'Darwinian selection' of rapidly growing cells that can endure survival pressures imposed by the host. A massive potential for glycan diversity exists, but a relatively limited array of glycans correlates with invasion and metastatic potential across a wide range of tumours.

Initial insight into the unique repertoire of glycans expressed on tumour cells emerged from the increased ability of tumours to bind a range of plant LECTINS.[5] Lectins exhibit protein folds that define families of carbohydrate-binding proteins that can bind in a specific 'lock-and-key' fashion.[6] Various endogenous animal lectins also exist, and these facilitate fundamental processes such as quality control of secreted proteins, cell-cell recognition, cell adhesion and motility, and pathogen-host recognition. Many lectins exist on the surface of immune cells and endothelial cells that line the vasculature, as ECM proteins and as soluble adhesion molecules such as mannose-binding proteins or galactose-binding lectins (galectins), and many of these can associate with tumour-cell-associated glycans. The interactions of lectins with tumour-cell glycans facilitate all aspects of tumour progression.

This article will mainly focus on examples in which genetic or pharmacological data confirm a correlation between a specific pattern of glycan expression and tumour progression. We have organized this review according to the main stages of tumour progression: proliferation, invasion, angiogenesis, metastasis and immunity (Fig. 2). We refer readers interested in more details to several excellent reviews on specific glycan classes and cancer.[3,7,8,9,10,11,12,13]

Stages of tumour progression.Tumour proliferation (a) is crucial at early stages of progression. b | During invasion, tumour cells gain the capacity to degrade, and migrate through, basement membranes and extracellular matrix. c | During the dissemination of tumour cells through the bloodstream, they aggregate with host cells such as platelets and lymphocytes and eventually lodge in the small vessels of distant organs. d | Tumour angiogenesis is required for pathological growth of the primary cancer and its metastases. Glycans have roles in each of these stages of tumour progression. See Fig. 3 for more details.

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