Mucins in cancer: protection and control of the cell surface

Key Points

  • The outermost area of a typical aerodigestive epithelial surface consists of secreted gel-forming mucins, and serves as a point of interface with air, food, enzymes, acid pH, salt, bacteria and viruses. The secreted mucin layer might also contact the cell surface through interactions with membrane-associated mucins or other cell-surface molecules.

  • Complex mucin gels have been shown to capture and hold biologically active molecules that might function as indicators of molecular or physical breach of the mucin layer and, following their release, might incite inflammatory, repair or healing processes.

  • Cell-surface-associated mucins are bound to cells by an integral transmembrane domain and have relatively short cytoplasmic tails that associate with cytoskeletal elements, cytosolic adaptor proteins and/or participate in signal transduction. Mucins might serve as cell-surface receptors and sensors, and conduct signals in response to external stimuli that lead to coordinated cellular responses that include proliferation, differentiation, apoptosis or secretion of specialized cellular products.

  • Cancer cells, especially adenocarcinomas, express aberrant forms or amounts of mucins. The expression of distinct oligosaccharide structures, together with differential glycosylation of mucin core proteins, confers on tumour cells an enormous range of potential ligands for interaction with other receptors at the cell surface.

  • Cancer cells might use mucins in much the same way as normal epithelia — for protection from adverse growth conditions and to control the local molecular microenvironment during invasion and metastasis.

  • Mucins are hypothesized to contribute to tumour invasion by simultaneously disrupting existing interactions between opposing cells (anti-adhesion) and establishing new ligands for interaction between the invading cell and the adjoining cells (adhesion).

  • Mucins could contribute to the regulation of differentiation and proliferation of tumour cells, through ligand–receptor interactions (for example, between MUC4 and ERBB2 (also known as HER2/neu) and morphogenetic signal transduction.

  • Two of the most widely used serum diagnostic assays for adenocarcinomas (CA19-9 and CA125) recognize epitopes that are found on mucins. Several immunologically based clinical-therapy trials target mucins that are expressed by adenocarcinomas, including monoclonal-antibody-based therapies and tumour vaccines.

Abstract

Mucins — large extracellular proteins that are heavily glycosylated with complex oligosaccharides — establish a selective molecular barrier at the epithelial surface and engage in morphogenetic signal transduction. Alterations in mucin expression or glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion and immune surveillance. Mucins are used as diagnostic markers in cancer, and are under investigation as therapeutic targets for cancer.

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Figure 1: Mucins control the molecular environment of aerodigestive epithelial-cell surfaces.
Figure 2: Membrane-associated mucins as receptors or sensors of the environment.
Figure 3: Signal transduction by membrane-associated mucins.
Figure 4: Tumours use mucins for invasion, metastasis and protection.
Figure 5: Anti-adhesion by membrane-associated mucins in cancer.
Figure 6: Adhesion by membrane-associated mucins in cancer.
Figure 7: Anti-immune and anti-inflammatory effects of mucins in cancer.

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Acknowledgements

Research in M.A.H.'s laboratory is supported by grants from the National Cancer Institute (NCI) of the National Institutes of Health. B.J.S. is supported by an NCI training grant and by the University of Nebraska Medical Center. The authors thank the reviewers and the following individuals for helpful suggestions and discussions: J. Anderson, S. Batra, T. Caffrey, J. Gum, A. Harris, A. Rizzino, X. Shen, P. Singh, J. Tremayne, H. Tsutsumeida, C. Yi, G. Suryanarayanan and Y. Wen. We acknowledge that this field of research is built upon the efforts of many and apologize to those authors not cited here because of the need for brevity.

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Correspondence to Michael A. Hollingsworth.

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colon cancer

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EGF

ERBB

ICAM-1

IL-1

IL-4

IL-6

IL-7

IL-9

IL-13

MUC1

MUC2

MUC4

MUC6

MUC7

MUC12

MUC13

MUC16

MUC17

MUC3A

MUC3B

MUC5AC

MUC5B

TACE

TNF-α

Glossary

TUMOUR-ASSOCIATED ANTIGEN

(TAA). An antigen that can evoke an immune response but is not unique to tumour cells. TAAs can arise from expression of developmentally restricted genes, overexpression of proteins that are normally expressed at low levels or post-translational modifications that give rise to unique epitopes.

BLOOD-GROUP ANTIGENS

Terminal oligosaccharides that are commonly found on proteins and glycolipids of red blood cells and leukocytes. They are also found on mucins and epithelial tumours.

O-GLYCOSYLATION

Chemical linking of monomeric carbohydrate moieties to the hydroxyl side group of serine and threonine residues of proteins. Mucin-type O-glycosylation is initiated by addition of a GalNAc residue to a serine or threonine, followed by sequential addition of carbohydrate residues. O-glycosylation is catalyzed enzymatically by glycosyltransferases, which act sequentially on specific substrates.

SULPHATION

An oligosaccharide modification in which a sulphate ester is chemically linked to the 6-hydroxyl group of GlcNAc or the 3-hydroxyl group of galactose. Sulphation has important roles in creating ligands for selectins and contributes to other ligand–receptor interactions.

STOICHIOMETRIC POWER

An effect created by densely arrayed repeating units of oligosaccharides (or other structures) that are attached to tandem repeats of mucin-type core proteins. The net effect is to create a locally high concentration of specific molecular structures.

THE TREFOIL MOTIF

Three loops that are formed by intrachain disulphide bonds in a 1–5, 2–4, 3–6 configuration between six conserved cysteine residues.

GOBLET CELLS

Specialized epithelial cells that secrete mucins by granular exocytosis.

INTRACELLULAR ADHESION MOLECULE-1

(ICAM-1). A member of the superfamily of immunoglobulin-like adhesion molecules, constitutively found on endothelial cells and some lymphocytes and monocytes. ICAM-1 has been shown to bind to extracellular MUC1 in vitro.

β-CATENIN

A member of the WNT signalling cascade. In cancer, β-catenin often accumulates in the nucleus where it binds to the TCF/LEF transcription factors to activate transcription. It has a key role in morphogenetic signal transduction, and interacts with several cell-surface adhesion molecules (cadherins) and with the cytoplasmic tail of MUC1.

MAPK PATHWAY

(Mitogen-activated protein kinase pathway). A signal-transduction pathway involving several kinases that is responsive to numerous external stimuli (growth factors, differentiation factors, other cellular conditions).

KIP1

A cyclin-dependent-kinase inhibitor. In response to DNA damage or anti-mitogenic signals, KIP1 binds to cyclin-dependent-kinase complexes and inhibits their function, thereby leading to cell-cycle arrest. Binding of MUC4 to ERBB2 increases expression of KIP1, which might lead to growth arrest.

SIGLECS

Sialic-acid binding immunoglobulin-like lectin proteins, which have important roles in mediating cell adhesion and other receptor–ligand events that involve oligosaccharide moieties.

SIALYL LEWIS A

Terminal oligosaccharide that is commonly overexpressed in cancer.

ENZYME-LINKED IMMUNOSORBENT ASSAY

(ELISA). A solid-phase immunoassay that detects the interaction between proteins and specific antibodies.

SIALYL TN

Short terminal oligosaccharide that is commonly synthesized in cancer cells but is not found in most normal tissues.

SIALYL LEWIS X

Terminal oligosaccharide that is commonly overexpressed in cancer.

RADIOIMMUNOCONJUGATES

Antibodies that are conjugated to radionuclides designed to bind to tumour antigens.

PASSIVE IMMUNOTHERAPY

The administration to a patient of pre-formed antibodies for an antigen to which the patient does not have an active immune response.

IMMUNOSCINTIGRAPHIC AGENT

An antibody that is conjugated to a radionuclide or chemical that can be given to patients and visualized in order to define tumour boundaries.

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Hollingsworth, M., Swanson, B. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4, 45–60 (2004). https://doi.org/10.1038/nrc1251

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