The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting

Abstract

The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among these are EphA2 and ephrinA1, which are involved in the development and maintenance of many different types of solid tumors. The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment. These variables affect the expression of the EphA2 and ephrinA1 proteins, the pathways through which they induce signaling, and the functional consequences of that signaling on the behavior of tumor cells and tumor-associated cells. This review will specifically focus on the roles that EphA2 and ephrinA1 play in the different cell types that contribute to the malignancy of solid tumors, with emphasis on the opportunities for therapeutic targeting.

FIGURE 1

Eph receptors and ephrin ligands. Schematic drawing of the localization, structural, and signaling components of (A) Eph receptors and (B) ephrinA and ephrinB ligands (141). P, tyrosine phosphorylation site. =, plasma membrane. Each color represents a structurally or functionally distinct domain of the protein, as labeled. Yellow in ephrinB ligands represents the intracellular, cytoplasmic tail of the protein. Adapted from Cytokine Growth Factor Rev, Vol. 13, N. Cheng, D.M. Brantley, J. Chen, The ephrins and Eph receptors in angiogenesis, pp. 75–85, Copyright (2002), with permission from Elsevier.

FIGURE 2

Hypothetical role of the EphA2/ephrinA1 system in solid tumor cells. EphA2 becomes overexpressed possibly due to increased gene expression or a lack of ephrinA1-induced receptor down-regulation. Overexpressed EphA2 is nonphosphorylated and stimulates oncogenic processes. EphrinA1 causes receptor phosphorylation and subsequent down-regulation, both of which likely contribute to the tumor-suppressing effects of the ligand in tumor cells. (−P), nonphosphorylated; (+P), phosphorylated.