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Glycosylation in cancer: mechanisms and clinical implications

Key Points

  • Glycosylation is a key cellular mechanism regulating several physiological and pathological functions. Alterations in glycoproteins, glycosphingolipids and proteoglycans are common features of cancer cells.

  • The most-widely occurring cancer-associated changes in protein glycosylation are increased sialylation, increased branched-glycan structures and overexpression of 'core' fucosylation.

  • The overexpression of branched-N-glycan structures interferes with epithelial cadherin-mediated cell–cell adhesion, promoting tumour cell dissociation and invasion.

  • Modifications of integrins with branched N-glycans, truncated O-glycans and/or sialylated structures modulate tumour cell–matrix interactions, fostering the process of tumour cell migration.

  • Altered expression of proteoglycans and their glycosaminoglycan chains interfere with extracellular signalling molecules and modulate the activation of tyrosine kinase protein receptors.

  • Altered glycosylation of growth factor receptors and the modified expression of gangliosides affect cancer cell signal transduction pathways, modulating tumour cell growth and proliferation.

  • Glycans and their corresponding endogenous carbohydrate-recognition lectins are key regulators of the inflammation and immune response towards the tumour cells.

  • Several serological markers currently used in the clinic are based on the detection of circulating glycoproteins or glycoconjugates with altered glycosylation.

  • Glycans have major potential applications in improving early diagnosis, determination of prognosis and risk stratification, as well as in serving as markers of specific therapeutic targets.

Abstract

Despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer. Glycobiology has been instrumental in relevant discoveries in various biological and medical fields, and has contributed to the deciphering of several human diseases. Glycans are involved in fundamental molecular and cell biology processes occurring in cancer, such as cell signalling and communication, tumour cell dissociation and invasion, cell–matrix interactions, tumour angiogenesis, immune modulation and metastasis formation. The roles of glycans in cancer have been highlighted by the fact that alterations in glycosylation regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention. This Review discusses the role of glycans in fundamental mechanisms controlling cancer development and progression, and their applications in oncology.

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Figure 1: Common classes of glycoconjugates in mammalian cells.
Figure 2: Schematic representation of important glycan structures.
Figure 3: Important tumour-associated glycans.
Figure 4: Role of glycans in cancer development and progression.

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Acknowledgements

The Institute of Molecular Pathology and Immunology of the University of Porto integrates the Institute for Research and Innovation in Health, which is partially supported by the Portuguese Foundation for Science and Technology (FCT). This work is funded by the European Regional Development Fund (FEDER) through the Operational Programme for Competitiveness Factors (COMPETE) and by national funds through the FCT, under the projects PEst-C/SAU/LA0003/2013, PTDC/BBB-EBI/0786/2012 and EXPL/BIM-MEC/0149/2012. S.S.P. acknowledges a grant from the FCT (number SFRH/BPD/63094/2009). C.A.R. acknowledges support from the European Union Seventh Framework Programme GastricGlycoExplorer (grant number 316929). The authors apologize that they cannot include all the relevant studies on glycosylation in cancer in this article owing to limitation of space. The authors thank Tiago Fontes-Oliveira for support in figures preparations.

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Glossary

Glycome

The entire complement of glycan structures in an organism.

Anomeric state

The configuration (α or β) of the hydroxy group originating from the aldehyde or ketone group after monosaccharide ring closure.

Sialic acid-binding immunoglobulin-type lectins

(Siglecs). Proteins that bind sialic acid.

N-glycans

Oligosaccharides covalently linked to an Asp residue of a protein (at the consensus sequence Asn-X-Ser/Thr, in which X is any amino acid) via a nitrogen atom. N-glycans are classified into high-mannose, complex and hybrid types.

O-glycans

Oligosaccharides that are linked to a polypeptide via an oxygen atom. O-glycans are classified according to the initiating monosaccharide linked to a Ser or Thr residue.

Glycosaminoglycan

(GAG). A linear co-polymer containing acidic disaccharide repeating units attached to proteoglycans via xylose linked to the hydroxyl group of a Ser residue8.

Chondroitin sulfate

A GAG chain containing acidic disaccharide repeating units of N-acetylgalactosamine β1-4 glucuronic acid (GlcNAcβ1-4GlcA). The GAG is called dermatan sulfate when the repeating units is N-acetylgalactosamine β1-4 iduronic acid (GlcNAcβ1-4IdoA).

Heparan sulfate

A GAG chain containing acidic disaccharide repeating units of N-acetylgalactosamine α1-4 glucuronic acid or iduronic acid (GlcNAcα1-4GlcA or GlcNAcα1-4IdoA).

Keratan sulfate

A GAG chain containing acidic disaccharide repeating units of galactose 1-β4-N-acetylglucosamine (Galβ1-4GlcNAc).

Glycosyltransferases

Enzymes that catalyse the transfer of saccharides (sugars) from activated donors to acceptor molecules (proteins, lipids or carbohydrates), forming covalent bonds.

Microdomain

A plasma membrane domain containing glycosphingolipids and proteins receptors influencing membrane fluidity, protein assembly and signalling.

O-GlcNAcylation

A covalent addition of N-acetylglucosamine (GlcNAc) to Ser or Thr hydroxyl moieties by O-GlcNAc transferase on nuclear and cytoplasmic proteins.

Tumour editing

Changes in tumour immunogenicity due to the antitumour response of the immune system, leading to emergence of immune-resistant cancer cell variants.

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Pinho, S., Reis, C. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer 15, 540–555 (2015). https://doi.org/10.1038/nrc3982

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