40% for patients whose tumors showed high cHIF-1α (B); and 59% for patients whose tumors showed low dVEGF-A vs. 40% for patients whose tumors showed high dVEGF-A (C). The 5-year survival rates were significantly shorter for patients whose Luminespib cell line tumors demonstrated low percentage of nHIF-1α and pVEGF-C and high percentage of cHIF-1α and dVEGF-A. Because tumor grading and staging are considered as major prognostic parameters in CCRCC, we first analyzed their impact on postoperative survival. We found a significant inverse association between survival and tumor grading (p < 0.001) or staging (p = 0.003). Univariate survival analysis showed

nuclear grade, pathologic stage, nHIF-1α and cHIF-1α expression as well as pVEGF-C and dVEGF-A to be significant predictive factors. However, on multivariate analysis only nuclear grade remained

significant EGFR phosphorylation (relative risk was 3 and 95% confidence interval 1.7–5.3), while pathologic stage (relative risk was 1.5 and 95% confidence interval 1–2.4) together with immunohistochemically analyzed proteins showed no independent prognostic value. Discussion There is a very large body of evidence that VEGF-A and related molecules such as VEGF-C and VEGF-D are potent proangiogenic factors GSK2126458 research buy involved in tumor growth and metastasis. Their intra-cell signaling pathway through specific receptors (VEGFRs) with tyrosine kinase activity provides targets for novel antiangiogenic designed drugs [10, 11, 17]. Our study demonstrated the expression of VEGF-A and VEGF-C on tumor cells but also in the cytoplasm of cortical Olopatadine tubular cells, endothelium, mesangium and macrophages,

which is consistent with literature reports [12–14, 18]. Endothelial-cell maintenance through regulated VEGF levels is crucial for glomerular function [19]. VEGF-C promotes survival in podocytes acting in an autocrine manner and both factors probably coordinate the synchronous development of the tubular and vascular architecture in the kidney required for the formation of the functioning nephron [12–14]. Similar to our previous work [15] on whole tumor slices, the heterogeneous expression of VEGF-A was also confirmed in TMA technique. Both angiogenic cytokines were immunohistochemically detected as heterogeneous staining of different intensity and percentage of positive tumor cells. Attention was especially focused on the pattern of their cytoplasmic distribution, diffuse and/or perimembranous, as previously reported by Yildis et al. [20] and Jacobsen et al. [21]. Jacobsen et al. believed that immunohistochemical VEGF expression near the cell membrane was affected by storage time of paraffin embedded tumor specimens and this type of VEGF expression was not further evaluated [21].