Experimental hypoxia does not influence gene expression and protein synthesis of Eph receptors and ephrin ligands in human melanoma cells in vitro.

Eph receptor tyrosine kinases and their ephrin ligands are considered to play important roles in melanoma progression and metastasis. Moreover, hypoxia is known to contribute to melanoma metastasis. In this study, the influence of experimental hypoxia on the expression and synthesis of EphA2 and EphB4, and their corresponding ligands ephrinA1, ephrinA5, and ephrinB2 was studied systematically in four human melanoma cell lines in vitro. Melanoma cell monolayer and spheroid cultures were used as both extrinsic and intrinsic hypoxia models. Hypoxic conditions were confirmed by analyzing hypoxia-inducible factors 1α or 2α expression, vascular endothelial growth factor expression, and cellular uptake of [F]fluoromisonidazole. In normoxia, EphA2, EphB4, ephrinA1, ephrinA5, and ephrinB2 expression was detectable in all cell lines to varying extents. Considerable protein synthesis of EphA2 was detected in all cell lines. However, no effect of experimental hypoxia on both Eph/ephrin expression and protein synthesis was observed. This contributes critically to the debate on the hypothesis that hypoxia regulates the Eph/ephrin system in melanoma.

Eph receptors and ephrin ligands: important players in angiogenesis and tumor angiogenesis.

Eph receptors and their ephrin ligands were identified in the late 1980's. Subsequently, they were linked to different physiological and pathophysiological processes like embryonic development, angiogenesis, and tumorigenesis. In this regard, recent work focused on the distribution and effects of Eph receptors and ephrins on tumor cells and tumor microenvironment. The purpose of this review is to outline the role of these molecules in physiological angiogenesis and pathophysiological tumor angiogenesis. Furthermore, novel therapeutical approaches are discussed as Eph receptors and ephrins represent attractive targets for antiangiogenic therapy.