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Beyond E-cadherin: roles of other cadherin superfamily members in cancer

Nature Reviews Cancer volume 14, pages 121–134 (2014)Cite this article

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Abstract

Loss of cadherin 1 (CDH1; also known as epithelial cadherin (E-cadherin)) is used for the diagnosis and prognosis of epithelial cancers. However, it should not be ignored that the superfamily of transmembrane cadherin proteins encompasses more than 100 members in humans, including other classical cadherins, numerous protocadherins and cadherin-related proteins. Elucidation of their roles in suppression versus initiation or progression of various tumour types is a young but fascinating field of molecular cancer research. These cadherins are very diverse in both structure and function, and their mutual interactions seem to influence biological responses in complex and versatile ways.

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Figure 1: Schematic overview of representative members of the cadherin superfamily with involvement in cancer.
Figure 2: Characteristic molecular interactions and biological activities of representative members of the cadherin superfamily within cancer cells.
Figure 3: Representative cadherin-mediated intercellular interactions that are involved in cancer.

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Acknowledgements

The author would like to thank A. Bredan for critical reading and editing of the manuscript, and his colleagues for helpful discussions. Research in the author's laboratory is supported by the Research Foundation — Flanders (FWO-Vlaanderen), the Foundation against Cancer (StK), Belgium, the Concerted Research Actions (GOA) of Ghent University, Belgium, and by the Belgian Science Policy (Interuniversity Attraction Pools — IAP7/07).

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  1. Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium. The Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,

    Frans van Roy

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Glossary

7D cadherins

(Seven-domain cadherins). A small cadherin family with two members (cadherin 16 (CDH16) and CDH17), each of which comprises seven extracellular cadherin repeats and a short cytoplasmic domain that is unable to bind to armadillo proteins.

Armadillo proteins

Proteins that contain tandem repeats of the armadillo domain. The first member of this family to be discovered was the Drosophila melanogaster protein armadillo — a homologue of many mammalian proteins, including β-catenin and p120-catenin, both of which bind to specific motifs in the cytoplasmic domains of classical cadherins.

Basal, suprabasal and simple epithelia

Epithelia occur as sheets of one layer thickness (simple epithelia) or as multiple layers (stratified epithelia), in which the basal layer rests on the basement membrane and is proliferative, whereas the suprabasal layers rest on the basal layer or on each other and undergo terminal differentiation.

Cell–cell adhesion mode

Adhesion can occur between cells of the same type (homotypic) or of different types (heterotypic); both binding modes can occur via molecules of the same type (homophilic) or of different types (heterophilic).

Classical cadherin

A member of a family of cadherins that comprises single-pass transmembrane proteins, which are characterized by tandem repeats of extracellular cadherin-specific domains, and by intracellular domains with two highly conserved binding sites for armadillo proteins, p120-catenin and β-catenin.

Desmosomes

Spot-like junction types, which tether the intermediate filament cytoskeleton to the plasma membrane and provide strong force-resistant mechanical properties to particular tissues such as epidermis and heart muscle. The intercellular adhesion in desmosomes is mediated by desmosomal cadherins.

Epithelial-to-mesenchymal transition

(EMT). A complex biological process in which genetic and epigenetic events lead to epithelial cells acquiring a mesenchymal gene activity signature and phenotype, which are often concomitant with increased cell migration. The process occurs in normal morphogenetic processes and in pathological situations.

GPI anchor

(Glycosylphosphatidylinositol anchor). A glycolipid that can be attached by posttranslational modification to the carboxyl terminus of particular extracellular proteins; this structure anchors those proteins to the exterior leaflet of the apical plasma membrane.

Morphogenesis

Used in this article to indicate that a particular cadherin is causally involved in processes of formation and organization of ordered tissues and organs. Morphogenesis implicates spatially and temporally regulated dynamical interactions of cells with their environment (or microenvironment), including neighbouring cells. The molecular mechanisms of cadherin-mediated morphogenesis are complex and partly unresolved.

Type I cadherins

Classical cadherins that are characterized by a relatively short ectodomain containing five extracellular cadherin repeats the elongated structure of which is stabilized by calcium ion binding; the most representative member is cadherin 1 (CDH1; also known as epithelial cadherin (E-cadherin)).

Type II cadherins

Classical cadherins that phylogenetically form a distinct branch from the type I cadherins. Compared to type I cadherins, their more deviating structure also results in more distant functions.

Vasculogenic mimicry

A mechanism of a plastic phenotypic change in aggressive cancer cells. It results in de novo formation of vascular networks by tumour cells, which thereby contribute to perfusion of rapidly growing tumours.

WAVE complex

Multiprotein complex consisting of five proteins, including a member of the Wiskott–Aldrich syndrome protein (WASP) family and NCK-associated protein 1 (NAP1). Various WAVE complexes function as scaffolds for numerous regulatory proteins that synergistically regulate the actin cytoskeleton and the plasma membrane shape and thus mediate outward cell protrusions and intracellular vesicular trafficking.

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van Roy, F. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer 14, 121–134 (2014). https://doi.org/10.1038/nrc3647

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