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Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Key Points

  • The Eph receptors are the largest family of receptor tyrosine kinases. They bind glycosylphosphatidylinositol (GPI)-linked and transmembrane ephrin ligands, generating bidirectional signals at sites of cell–cell contact.

  • Eph receptors and/or ephrins are widely expressed in cancer cells and tumour stroma, but they can be downregulated at advanced cancer stages. Often Eph receptor and ephrin levels are discordantly regulated. In addition to changes in expression levels, Eph receptor mutations are also likely to have a role in cancer pathogenesis.

  • In many cellular contexts, Eph bidirectional signalling promotes an epithelial phenotype and suppresses cancer cell–substrate adhesion, migration, invasion and growth. Consistent with this, Eph receptor signalling seems to be low in many cancer cells owing to an imbalance of Eph and ephrin expression or the inability of receptor and ligand to interact effectively.

  • Eph receptors and ephrins can also promote cancer progression through poorly understood mechanisms that do not involve reciprocal association but rather depend on crosstalk with oncogenic signalling pathways. In addition, Eph bidirectional signals promote tumour angiogenesis.

  • Eph receptors and ephrins are promising new therapeutic targets in cancer, and many Eph-based approaches show promise for prognosis and therapy.

Abstract

The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression. Eph gene mutations probably also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth, migration and invasion of cancer cells in culture as well as tumour growth, invasiveness, angiogenesis and metastasis in vivo. However, Eph signalling activities in cancer seem to be complex, and are characterized by puzzling dichotomies. Nevertheless, the Eph receptors are promising new therapeutic targets in cancer.

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Figure 1: Eph receptor and ephrin domain structure and signalling interactions.
Figure 2: Eph feedback loops.
Figure 3: Tumour suppression through bidirectional signalling.
Figure 4: Eph tumour promoting pathways.

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Acknowledgements

The author thanks members of her laboratory for helpful comments on the manuscript. Work in the author's laboratory is supported by grants from the US National Institutes of Health, the Department of Defense, the Tobacco-Related Disease Research Program, and Sanford Children's Health.

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DATABASES

ClinicalTrials.gov 

EPHA2 clinical trials

EPHB4 clinical trials

NCT00796055

National Cancer Institute Drug Dictionary 

dasatinib

trastuzumab

FURTHER INFORMATION

Elena B. Pasquale's homepage

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cancer GeneticsWeb

Catalogue of somatic mutations in cancer

NCBI Human Genome Resources

Glossary

Basal phenotype

Highly aggressive breast and prostate cancers with gene expression profiles similar to basal cells. Basal-type breast cancers are typically negative for oestrogen, progesterone and ERBB2 receptors. Basal-type prostate cancers have high expression of cytokeratin 5 and low expression of androgen receptor and prostate-specific antigen.

Nonsense-mediated mRNA decay

The process by which mRNA molecules carrying premature stop codons are degraded by a regulated pathway, thereby limiting the synthesis of abnormal proteins.

Cyclic stretch

Periodic stretch (or strain) to which vascular endothelial cells are subjected as a result of the rhythmic changes in vessel diameter caused by pulsatile blood flow.

Shear stress

The physical force exerted on endothelial cells as a result of blood flow.

Pericytes

Mesenchymal cell precursors to vascular smooth muscle that associate with endothelial cells during angiogenesis and provide support to small capillaries.

Apc Min/+

Mouse that carries the multiple intestinal neoplasia (Min) point mutation in one Apc allele and spontaneously develops intestinal adenomas. Commonly used model for human familial adenomatous polyposis and human sporadic colorectal cancer.

Mesenchymal-to-epithelial transition

The conversion of non-polarized and motile mesenchymal cells into polarized epithelial cells. Typically associated with increased E-cadherin levels and low cancer cell invasion and metastasis. It is the reverse of the better known epithelial-to-mesenchymal transition.

Ameboid-type migration

Motility frequently exhibited by cancer cells and leukocytes that is characterized by high speeds, lack of stable polarity and a relatively amorphous cell shape. Does not require stable integrin-dependent adhesion for traction but depends on RHOA to increase actomyosin contractility and allow invasion in the absence of extracellular proteolysis.

Mesenchymal-type migration

Movement of cells with elongated morphology and a front-back polarity, with traction generated through integrin-dependent adhesion. Requires extracellular proteolysis for cell invasion and is thought to depend on RAC1.

Vasculogenic mimicry

The formation by the tumour cells of blood vessel-like channels that contribute to tumour blood perfusion.

Apico-basal polarization

Epithelial cells are polarized, with an apical membrane that faces the external environment or a lumen and is opposite the basolateral membrane, which functions in cell–cell interactions and contacts the basement membrane.

'Dependence' receptors

Structurally unrelated receptors that can induce cell death by apoptosis when unoccupied by ligand, thus creating cellular dependence on their ligands. In the presence of ligand, these receptors mediate survival, differentiation or migration.

Neutral liposomes

Small vesicles made of neutral phospholipids (such as DOPC, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine), which can be filled with small interfering RNA for efficient in vivo intracellular delivery to tumour tissue.

Radioimmunopositron emission tomography (PET) imaging

PET imaging using a radioactively labelled antibody. It allows non-invasive in vivo visualization of a tissue of interest, such as tumour tissue, that expresses the antigen as well as quantification of antigen levels.

Gamma camera imaging

Imaging with a camera that detects radioisotopes emitting gamma radiation. It is also known as scintigraphy and allows non-invasive in vivo visualization of radioisotopes coupled, for example, to an antibody that targets tumour tissue.

Epithelial-to-mesenchymal transition

A complex process in which genetic and epigenetic events lead to epithelial cells acquiring a mesenchymal architecture concomitant with increased cell motility. Typically associated with the loss of E-cadherin expression, disruption of cell–cell junctions, and cancer cell invasion and metastasis.

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Pasquale, E. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10, 165–180 (2010). https://doi.org/10.1038/nrc2806

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