Classification of renal cell carcinoma based on expression of VEGF and VEGF receptors in both tumor cells and endothelial cells

Recent development of antiangiogenic therapy for renal cell carcinoma ( RCC) has significantly improved the treatment of these often refractory tumors. However, not all patients respond to therapy and assays for predicting outcome are needed. As a first step, we analyzed a retrospective cohort of tumors and assessed the ability of VEGF and VEGF receptors ( VEGF- R1, - R2 and - R3) to classify tumors. We analyzed tissue microarrays containing 330 RCCs using a novel method of automated quantitative analysis of VEGF and VEGF- R expression by fluorescent immunohistochemistry. Expression of markers was separately quantified within three tissue components: tumor cells, endothelial cells and adjacent normal epithelium. VEGF and VEGF receptors were tightly coexpressed both within tumors and within adjacent normal cells ( all P- values o0.001). Tumor cell expression of VEGF- R1 and - R2 was strongly and inversely correlated with vessel area ( Po0.0001). Unsupervised hierarchical clustering classified tumors by coordinated expression of VEGF and VEGF- Rs. The distribution of clear cell and papillary tumors was not significantly different between clusters. Clusters with high expression of VEGF and VEGF- Rs in the tumor cells exhibited poor survival when compared with the other clusters on uni- and multivariable analysis. VEGF and VEGF receptors exhibit a complex pattern of coordinated expression in RCC. Clustering tumors by VEGF and VEGF- R in tissue components demonstrates distinct tumor phenotypes with different outcomes, and may provide a means for determining which tumors will respond to what antiangiogenic therapies.