Roles of EphA1/A2 and ephrin-A1 in cancer

Abstract

The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up- or down-regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin-A1 that is a membrane-anchored ligand for EphAs was co-localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin-A1-induced lung metastasis by understanding the physiological function of ephrin-A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin-A1 in tumors and an establishment of pre-metastatic microenvironment in the lungs.

Keywords: ADAM; Eph; S100A8; ephrin; metastasis.

Figure 1

Activation mechanism of the Eph/ephrin system. Ephrin‐As anchored by GPI to the plasma membrane bind to EphAs in adjacent cell. This type of activation mechanism is called juxtacrine. EphAs and ephrin‐As simultaneously transmit their signals into each cell termed as forward and reverse signal, respectively

Figure 2

Regulation mechanism of ECM/integrin/EphA1‐mediated cell adhesion. A, Co‐immuno‐precipitation of EphA1 and integrin β1. GFP‐fused EphA1‐expressing HEK293 cells were stimulated with Fc‐ephrin‐A1 (2 μg/mL). EphA1 was co‐immuno‐precipitated with integrin β1 without affecting tyrosine phosphorylation status of EphA1. B, Regulatory signaling pathway of ECM/integrin/EphA1‐mediated cell adhesion. In the absence of ephrin‐A1 stimulation, ILK is in active. ECM/integrin signal provides cell spreading mediated by Rac1 activation. Once EphA1 is stimulated with ephrin‐A1, ILK is inactivated. Subsequently, the Rac1 GTP‐bound form is hydrolyzed by Rac1 GTPase activating protein followed by RhoA activation, which in turn induces cell retraction

Figure 3

Role of the EphA1/A2 and ephrin‐A1 system in tumors and lung metastasis. A, Cell boundary formation by the Eph/ephrin system. The Eph/ephrin system provides cell‐cell contacts via receptor‐ligand interaction. Co‐culture of EphA1‐DsRed‐ and YFP‐ephrin‐A1‐ expressing cells (E‐cadherin‐negative HEK293 cells) induced boundary formation. The cells kept sitting together on a culture dish (upper panel of pictures). TGFβ‐induced ADAM12 activation leads to endocytosis of the Eph/ephrin complex by its protease activity. In our hypothesis, loss of Eph/ephrin‐mediated cell‐cell contacts render tumor cells free to move for metastasis (lower panel of pictures). Scale Bars: 10 μm. B, An enhancement of lung vascular permeability by breakdown of the Eph/ephrin system. ADAM12 localizes in vascular endothelial cells. Activated ADAM12 may cleave membrane‐anchored ephrin‐A1 joining to boundary formation. The cleavage induces endocytosis and RhoA activation leading to cell retraction. Cleaved ephrin‐A1 competes for pre‐existing Eph/ephrin interactions. Ephrin‐A1‐stimulated vascular endothelial cells are shrunk, and thereby enhances lung vascular permeability

Figure 4

A proposed paracrine loop to establish pre‐metastatic microenvironment in lungs. Ephrin‐A1 expression is enhanced by the TLR4/S100A8 axis. ADAM12 is up‐regulated by inflammatory cytokines such as TNFα and TGF‐β1. Cleaved ephrin‐A1 enters into blood stream and stimulates lung vascular endothelial cells leading to an elevation of CCL2 secretion. The CCR2/CCL2 axis contributes to an increase of SAA3 and S100A8/S100A9 expression. The paracrine loop increases permeability factors enclosed by red box, and then tumor metastasis are facilitated in the lungs. Up‐regulated S100A8/A9 expression in endothelial cells and leukocytes may increase ephrin‐A1 expression mediated by TLR4 and/or EMMPRIN in primary tumors