EphA2 protein expression in metastatic renal cell carcinoma treated with VEGF-inhibitors is predictive of patient survival

Abstract

Background: EphA2 is a receptor tyrosine kinase of the Eph family, which regulates angiogenesis, cell growth, survival and migration. EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein, particularly in case of resistance to VEGF-targeted therapy. This work raised the question whether EphA2 expression would be a predictive factor in patients with metastatic renal cell carcinoma (RCC) treated with VEGF inhibitors. Methods: We analyzed the levels of EphA2 protein expression by immunohistochemistry in specimens of 23 patients with metastatic RCC, which were postsurgically treated with Anti-VEGF-therapy. The quantification of EphA2 protein expression was performed by automated digital image analysis using the open source software ImageJ. Statistical analysis using Cox proportional hazard modeling, Bayesian information criterion (BIC) statistic and Kendall’s tau ( τ ) correlation was done using the program R. Results: The expression of EphA2 correlated significantly with the histological grading (correlation coefficient Kendall’s τ =0.52; p <0.05 for grades II and III). High levels of EphA2 expression levels by the adjacent kidney tissue of RCC tumors had a positive predictive value for overall survival, suggesting a tumor suppressive effect of EphA2 expressed in the tumor surrounding tissue. We also found a negative correlation between the EphA2 expression level in the primary tumor and the matching metastasis. These findings implicate different dominating signaling pathways in the primary tumor and its metastasis, with consequently a need for a complex therapeutic approach. Conclusions: Our study suggests an association between EphA2 receptor expression and RCC carcinogenesis and metastasis. The differential effects of EphA2 signaling, from a tumor suppressive to a tumor promoting role, are greatly dependent upon its precise localization: In addition to its previously described tumor promoting role in EphA2 overexpressing tumors we observed an association between high levels of EphA2 in the adjacent normal kidney tissue and survival, suggesting a tumor suppressive role. An improved understanding of the different tasks of EphA2 signaling in the primary tumors, their surrounding tissues and metastases may be of benefit for a better targeting of metastatic RCC.