Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Abstract

The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumor blood vessels, which suggest important roles for their bidirectional signals in multiple aspects of cancer development and progression. Eph gene mutations likely also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth and migration/invasion of cancer cells in culture as well as tumor growth, invasiveness, angiogenesis, and metastasis in vivo. However, Eph signaling activities in cancer appear to be complex, and are characterized by puzzling dichotomies. The Eph receptors nevertheless represent promising new therapeutic targets in cancer.Eph receptors and their ephrin ligands together form an important cell communication system with widespread roles in normal physiology and disease pathogenesis 1 . Links between Eph receptors and cancer date back to the first identified Eph family member 2 . EphA1 was cloned from a carcinoma cell line in a screen for novel oncogenic tyrosine kinases. The novel receptor was found to be upregulated in tumor versus normal tissues and its overexpression caused the oncogenic transformation of NIH3T3 fibroblasts 2,3 . The first Eph receptor-interacting (ephrin) ligand, EPHRIN-A1, was also identified from cancer cells a few years later 4 . The evidence implicating Eph receptors and ephrins in cancer is now extensive, and continues to grow.The activities of the Eph system in cancer are complex, and intriguing in their paradoxical effects. For example, multiple Eph receptors and/or ephrins are present in essentially all types of cancer cells. However, not only increased but also decreased Eph expression has been linked to cancer progression. Consistent with this dichotomy, there is good evidence that Eph receptors and ephrins can both promote and inhibit tumorigenicity. The factors responsible for these divergent activities are only beginning to be uncovered.Following a brief overview of the Eph and ephrin families and their bidirectional signaling mechanisms, the factors that regulate their expression and the remarkable multiplicity of their roles in cancer will be discussed, and the strategies under evaluation to target the Eph system for cancer therapy outlined. Other reviews provide more in depth information on Eph signaling mechanisms in development and adult physiology 1,[5][6][7][8] . Eph and ephrin familiesIn the human genome there are 9 EphA receptors, which promiscuously bind 5 glycosylphosphatidylinositol (GPI)-linked ephrin-A ligands, and 5 EphB receptors, which NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2010 September 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript promiscuously bind 3 transmembrane ephrin-B ligands 5 . Exceptions are the EPHA4 and EPHB2 receptors, which can also bind ephrin-Bs and EPHRIN-A5, respectively, and EPHB4, which preferentially binds only EPHRIN-B2. Eph receptors typically interact with the cell surface...

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

“…The activation of tyrosine kinase signaling suggests the presence of alternative mechanisms regulating tyrosine kinase activity not related to activating mutations (18,21,22). These include but are not limited to loss of negative feedback mechanisms (e.g., increased or decreased phosphatase activity), transcriptional up-regulation of kinases, or increased stabilization of tyrosine kinases through decreased protein degradation (22,41,42). Our data suggest that some of these mechanisms may control tyrosine kinase signaling in our mouse model of prostate cancer.…”

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

“…We observe that the axon guidance pathway (ephrins, netrins, semaphorins and slits) was mutated in 59% (N ¼ 29) of the GC tumours. Frequent and exclusive mutations were grouped into the Ephrins and SLIT/ROBO pathway genes 30,31 (Fig. 4b).…”

Anoikis: an emerging hallmark in health and diseases

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