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The sweet and sour of cancer: glycans as novel therapeutic targets

Key Points

  • Tumours aberrantly express various glycans. Glycans regulate many different aspects of tumour progression, including proliferation, invasion, angiogenesis and metastasis.

  • The proliferation of tumour cells is potentiated by the ability of glycoproteins and glycosphingolipids to directly activate growth-factor receptor tyrosine kinases and by the ability of proteoglycans to function as co-receptors for soluble tumour growth factors.

  • The overexpression of specific glycosyltransferases by tumour cells promotes the formation of tumour glycans that facilitate invasion.

  • Carcinomas commonly overexpress O-linked glycans in the form of cell-surface and secreted mucins that present ligands for adhesion receptors, such as the selectins, which promote the ability of tumour cells to interact with host platelets, leukocytes and endothelial cells. These interactions facilitate haematogenous metastasis of tumour cells.

  • Glycosphingolipids, in the form of gangliosides, are overexpressed by a range of tumours, and their shedding into the bloodstream might impair host immunity to some tumours.

  • During tumour proliferation and invasion, heparan-sulphate proteoglycans (HSPGs) that are present on the surface of tumour cells function as co-receptors to stabilize growth-factor receptor signalling complexes. Secreted HSPGs that are present in the extracellular matrix store growth factors that can be mobilized by the action of tumour heparanases. A similar mechanism that involves endothelial-associated HSPGs and endothelial growth factors facilitates vascular sprouting during tumour angiogenesis.

  • Some glycans can be measured in the bloodstream, and their use as markers of disease burden can be used to screen for specific cancers as well as track response to therapy.

  • Experiments in which glycan function is genetically altered in cell-culture systems or mouse tumour models validate their potential as targets for anticancer therapy.

  • A few glycan-based targeting strategies are currently being tested in clinical trials. As we learn more about the roles of glycans in tumour progression, new targets will continue to emerge for drug design.

Abstract

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.

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Figure 1: Important glycans involved in tumour progression.
Figure 2: Stages of tumour progression.
Figure 3: Glycans participate in major pathophysiological events during tumour progression.

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Acknowledgements

We would like to thank A. Varki for many helpful comments. This work was supported by a Research Career Development Award from the US Department of Veteran's Affairs (to M.F.) and National Institutes of Health (to J.D.E.).

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DATABASES

Entrez Gene

CD44

COSMC

E-cadherin

EGF

ERBB2

FGF2

glypican-1

glypican-3

HB-EGF

IGF1R

IL-8

MUC1

MUC16

MUC4

TGFβ

VEGF

National Cancer Institute

breast cancer

melanoma

ovarian cancer

pancreatic cancer

FURTHER INFORMATION

Complex Carbohydrate Research Center

Consortium for Functional Glycomics

Glycobiology journal

Glycobiology Research and Training Center

National Cancer Institute Glycobiology Resources

Oxford Glycobiology Institute

Society for Glycobiology

Glossary

GLYCOCONJUGATE

A molecule in which one or more glycan units are covalently linked to a non-carbohydrate entity.

N-LINKED GLYCANS

Glycans covalently linked to an asparagine residue of a polypeptide chain in the consensus sequence–Asn–X–Ser/Thr.

GLYCOPROTEIN

A protein with one or more covalently bound glycans.

O-LINKED GLYCANS

Glycans glycosidically linked to the hydroxyl group of the amino acids serine, threonine, tyrosine or hydroxylysine.

MUCINS

Large glycoproteins with a high content of serine, threonine and proline residues, and numerous O-linked glycans, often occurring in clusters on the polypeptide. Tumour mucins are often decorated by unique small glycans such as Tn (O-linked GalNAc) or sialyl Tn antigens (sialic acid-capped O-linked GalNAc).

PROTEOGLYCAN

A protein with one or more covalently attached glycosaminoglycan chains, such as heparan sulphate or chondroitin sulphate (and dermatan sulphate). In the tumour environment, a range of heparan-sulphate proteoglycans expressed by both tumour cells as well as endothelial cells affect growth-factor signalling.

GLYCOCALYX

The cell-coat structure consisting of glycans and glycoconjugates surrounding animal cells. This is seen as an electron-dense layer by electron microscopy.

LECTIN

A protein (other than an anti-carbohydrate antibody) that specifically recognizes and binds to glycans without catalysing a modification of the glycan.

EGF-RECEPTOR FAMILY

Epidermal growth factor receptors have important roles in initiating the signalling that directs the behaviour of epithelial cells and tumours of epithelial origin. The four members of the family are also known as ERBB receptor tyrosine kinases (ERBB1–4), and share structural and functional similarities.

GANGLIOSIDES

Anionic glycosphingolipids containing one or more residues of sialic acid.

LIPID RAFTS

Microdomains in the plasma membrane that are enriched in sphingolipids, cholesterol and GPI-linked proteins. They function as signalling platforms through their ability to concentrate signalling proteins, resulting in increased output from receptors that require cross-activating interactions and increasing local concentrations of other downstream signalling components.

SELECTINS

C-type calcium-dependent lectin expressed by cells in the vasculature and bloodstream. The three known selectins are L-selectin/CD62L (expressed by most leukocytes), E-selectin/CD62E (expressed by cytokine-activated endothelial cells) and P-selectin/CD62P (expressed by activated endothelial cells and platelets). Important ligands for the selectins include glycans containing sialyl Lewis X and sialyl Lewis A.

METASTATIC SEEDING

The colonization of an organ or tissue by metastatic tumour cells.

LEWIS TYPE BLOOD GROUP ANTIGENS

A structurally similar set of fucose-containing (α1-3-fucosylated) oligosaccharides found on normal epithelia and blood cells, a few of which (for example, the sialyl Lewis X or sialyl Lewis Y antigens) are overexpressed on the surface of certain epithelial tumour cells.

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Fuster, M., Esko, J. The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer 5, 526–542 (2005). https://doi.org/10.1038/nrc1649

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