Ephrins are cell surface-associated proteins important for development, especially in cell-cell interactions involved in nervous system patterning (axon guidance), angiogenesis, and oncogenesis.1-5 Ephrins can be classified into two groups, A and B, based on structure and function, with preference to the EphA and EphB receptor subgroups, respectively.1-3,6 Ephrin-A1 is a member of the A group of Ephrins, which are anchored to the cell via a glycosylphosphatidylinositol (GPI) linkage.4,6-7 Although originally identified as a ligand for EphA2,8 Ephrin-A1 can bind seven different Ephs (EphA1-EphA7).3
In melanoma cell lines, Ephrin-A1 can act as a growth factor. The proliferative response to Ephrin-A1 correlates with the expression of the EphA2 receptor.9 Melanoma cell lines can also express Ephrin-A1, suggesting the possibility of an autocrine growth pathway with the expression of both receptor and ligand on these cells.9 Collectively, these results raise the question of the role of Ephrin-A1 in melanoma development in vivo and disease prognosis in general.
Analyses of Ephrin-A1 and EphA2 expression in melanoma biopsies of different stages by Northern blot analysis, in situ hybridization, and immunohistochemistry yield mixed results.10 Although EphA2 mRNA can be detected in biopsies, amounts vary and do not increase with melanoma progression.10 Additionally, patient follow-up data demonstrate no correlation between expression of EphA2 and prognosis.10 In contrast, both immunoblot analysis and immunohistochemical staining detect increasing amounts of Ephrin-A1 with more advanced melanoma lesions, suggesting a role for Ephrin-A1 in melanoma progression.10 Up-regulation of expression of Ephrin-A1 may be associated with expression of host inflammatory responses to advanced lesions. For example, the pro-inflammatory cytokines, TNF-alpha and IL-1 beta, both induce Ephrin-A1 expression in melanoma cells.10
The question still remains, however, as to what specific role Ephrin-A1 plays in melanoma progression. Ephrin-A1 expression may confer a selective advantage to tumors that express it due to its angiogenic activity.11 Easty et al.10 have hypothesized that Ephrin-A1 production may promote vascularization of the tumor, facilitating further growth and potential metastasis of the tumor. In addition, although expression of the Ephrin-A1 receptor EphA2 did not correlate with up-regulation of Ephrin-A1 in melanoma progression in vivo, it is possible that one or more of the other EphA receptors could be mediating the Ephrin-A1 response. In order to discern the involvement of Ephrin-A1 in melanoma growth and progression, additional research must be done to evaluate involvement of other receptors it may be working through as well as what cytokines may be playing supporting roles.