There is currently an urgent need for development of alternative, effective diagnostic and therapeutic approaches to GBM. The survival of patients with GBM may depend on the identification of novel targets. EphA2 receptor has already been recognized as a potential molecular marker and target in GBM for the development of novel biological therapeutic agents [
22,
23,
33]. Whereas several studies in recent years have clearly indicated that altered expression of Eph receptors and ephrin ligands is associated with increased potential for tumor growth, angiogenesis, metastasis and adverse outcome [
34‐
42], few studies have addressed the role of EphA7 in tumor pathogenicity. By employing immunohistochemical techniques we have found that EphA7 protein is predictive for the outcome of patients with GBM, independent of MVD expression. The data in the present study revealed for the first time a strong correlation between EphA7 overexpression and patient survival.
Hafner C, et al. found that EphA7 is highly expressed in kidney vasculature [
43]. The mRNA of EphA7 is strongly upregulated in hepatocellular carcinoma as compared with healthy liver tissue and is downregulated in colon carcinomas. EphA7 is also transcriptionally activated in lung cancer [
44]. Furthermore, overexpression of EphA7 protein is frequently found in younger patients and in patients with advanced gastric carcinoma [
45]. EphA7 expression is frequently silenced in human colorectal carcinoma by aberrant promoter methylation [
46]. EphA7 is located on 6q16.1, a region in close proximity to the chromosome 6 breakpoint found in various types of cancer [
47]. Although our findings are not consistent with Wang et al, who found a significant downregulation of EphA7 in colorectal carcinoma [
46], they are in line with previous reports reporting a tumor promoter role in lung cancer and hepatocellular carcinoma [
43,
44], implicating tumor type-specific function for different Eph family members. Eph receptors expressed in different cell types may have opposite effects due to cell-type specific intracellular signaling pathway [
4]. Indeed, EphB4 receptor has been identified as a tumor suppressor in breast cancer, through activation of Abl-Crk antioncogenic pathway [
48], while the same receptor presented a tumorigenic potential in mesothelioma, favoring uncontrolled cell growth, migration, and tumor progression [
49]. Moreover, membrane-bound ephrins trigger Eph receptor phosphorylation, while soluble forms can bind to Eph receptor, but do not trigger receptor activation [
50]. Murine and human peripheral lymphocytes secrete a truncated form of EphA7 [
51]. Truncated Eph receptors retaining their ligand-binding capacity have been shown to block activation of the full-length receptor [
52]. Promoter hypermethylation and silencing of EphA7 in mature B-cell lymphomas may serve to eliminate the inhibitory activity of secreted EphA7 on tumor-promoting EphA7 receptor signaling, thus enhancing tumor cell spread and recruitment of accessory cells able to promote tumor growth [
51]. A recent study on signaling pathways involved in EphA7 RTK reported that direct EphA7 knockdown can result in attenuation of ERK1/2 phosphorylation and induce apoptosis of leukemia cells, suggesting the impact of EphA7 on the growth of tumor cells [
45]. It is of interest that positive EphA7 expression was closely associated with increased age of patients (>55 years). Whether this is a random finding or not deserves further investigation.
The unfavorable prognostic influence of EphA7 in GBM could be attributed to the well-recognised role of Eph RTKs in tumor angiogenesis. Indeed, in this study a statistically significant correlation between expression of EphA7 and MVD was noted in GBM specimens. Another important observation was EphA7 overexpression in both vasculature as well as tumor cells. The process of angiogenesis plays a central role in tumor growth and in the development of distant metastases by facilitating the entry of cells into circulation [
52‐
55]. A vast biochemical and genetic evidence has implicated the critical role of Eph/ephrin signaling in angiogenesis, despite of VEGFR2 and Tie2 receptors long been recognized as key players in this process [
53,
54]. Angiogenetic activity can be measured histologically by MVD, which has been shown to be an independent prognostic parameter in various malignancies including gliomas [
56‐
58]. However, other studies on angiogenesis of glioblastomas suggested the limited usage of MVD as prognostic parameter due to the complexity of the microvascular network in GBM [
59,
60]. Although no correlation between MVD and overall survival or recurrence-free survival was found in our study, we observed a statistically significant correlation between lower MVD and tumor recurrence. Further prospective studies with large numbers of patients are, however, needed to fully clarify the clinical implications of MVD in GBM recurrence.