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The role of glycans in the development and progression of prostate cancer

Nature Reviews Urology volume 13, pages 324–333 (2016)Cite this article

Subjects

Key Points

  • Glycosylation is a key cellular mechanism regulating many important biological processes in cancer; alterations in glycosylation patterns are common features of cancer cells

  • The prostate is a secretory gland with an important role in male fertility, and as such, is an abundant secretor of glycoproteins of all types

  • A variety of alterations in glycoproteins have been observed in prostate cancer cells including: increased sialylation and fucosylation; increased O-β-N-acetylglucosylation; the emergence of cryptic and high-mannose N-glycans and proteoglycan alterations

  • Glycosylation-specific antibodies and glycosylation gene signatures have proven to be powerful tools in classifying prostate cancer tumour aggressiveness

  • Glycans have potential clinical applications in patients with prostate cancer as both predictive and prognostic biomarkers and therapeutic targets

Abstract

Prostate cancer is a unique and heterogeneous disease. Currently, a major unmet clinical need exists to develop biomarkers that enable indolent disease to be distinguished from aggressive disease. The prostate is an abundant secretor of glycoproteins of all types, and alterations in glycans are, therefore, attractive as potential biomarkers and therapeutic targets. Despite progress over the past decade in profiling the genome and proteome, the prostate cancer glycoproteome remains relatively understudied. A wide range of alterations in the glycoproteins on prostate cancer cells can occur, including increased sialylation and fucosylation, increased O-β-N-acetylglucosamine (GlcNAc) conjugation, the emergence of cryptic and high-mannose N-glycans and alterations to proteoglycans. Glycosylation can alter protein function and has a key role in many important biological processes in cancer including cell adhesion, migration, interactions with the cell matrix, immune surveillance, cell signalling and cellular metabolism; altered glycosylation in prostate cancer might modify some, or all of these processes. In the past three years, powerful tools such as glycosylation-specific antibodies and glycosylation gene signatures have been developed, which enable detailed analyses of changes in glycosylation. Thus, emerging data on these often overlooked modifications have the potential to improve risk stratification and therapeutic strategies in patients with prostate cancer.

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Figure 1: Representative mammalian O-linked and N-linked glycans.
Figure 2: The four most common biantennary N-linked glycan structures detected on PSA asparagine-69.
Figure 3: Schematic representation of glycan structures produced by incomplete and/or neo-synthesis.
Figure 4: Induction of the cancer-associated sialyl-Tn (sTn) antigen by androgens in prostate cancer cells.
Figure 5: Structural examples of branched and cryptic N-glycans detected in prostate cancer tissue samples.
Figure 6: The hexosamine biosynthetic pathway (HBP).

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Acknowledgements

This work was funded by Prostate Cancer UK (PG12-34), The J.G.W Patterson Foundation, The Wellcome Trust (grant numbers WT080368MA and WT089225/Z/09/Z) and BBSRC (grant BB/1006923/1 and BB/J007293/1). I.G.M is supported in Belfast by the Belfast-Manchester Movember Centre of Excellence (CE013_2-004), funded in partnership with Prostate Cancer UK.

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Authors and Affiliations

  1. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    Jennifer Munkley & David J. Elliott

  2. Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Forskningsparken, Gaustadalléen 21, Oslo, N-0349, Norway

    Ian G. Mills

  3. Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital HE - Norwegian Radium Hospital, Montebello, NO-0424, Oslo, Norway

    Ian G. Mills

  4. Movember/Prostate Cancer UK Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK

    Ian G. Mills

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  1. Jennifer Munkley
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Contributions

J.M. researched data for this article, J.M. and D.E. made a substantial contribution to discussions of content, J.M. and I.G.M. wrote the manuscript and all authors edited and/or reviewed the manuscript prior to submission.

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Correspondence to Jennifer Munkley.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Glycoproteins

Proteins modified by one or more glycans.

Glycans

The carbohydrate moieties of a glycoprotein, glycolipid or a proteoglycan.

O-linked glycans

Oligosaccharides that are covalently linked to a serine or threonine residue via an oxygen atom.

N-linked glycans

Oligosaccharides covalently linked to an asparagine residue of a protein via a nitrogen atom.

Glycome

The global collection of glycans (sugar chains) synthesized by a cell.

Glycosyltransferases

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

Lectins

Carbohydrate binding proteins that are highly specific for sugar moieties.

Glycolipid

A lipid modified by one or more glycans.

Proteoglycans

Proteins with one or more glycosaminoglycan (GAG) chains, such as chondroitin sulfate and heparin sulfate. Proteoglycans constitute a large fraction of the extracellular matrix and have key roles in cell adhesion and motility.

O-GlcNAcylation

Addition of N-acetylglucosamine (GlcNAc) to serine or threonine residues on nuclear and cytoplasmic proteins.

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Munkley, J., Mills, I. & Elliott, D. The role of glycans in the development and progression of prostate cancer. Nat Rev Urol 13, 324–333 (2016). https://doi.org/10.1038/nrurol.2016.65

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