Namely, diffuse and intensive cytoplasmic VEGF-A and -C staining was associated with higher Sapitinib datasheet nuclear grade, larger tumor size, higher tumor stage and higher cHIF-1α. There are not so many reports on VEGF-C expression in CCRCC. Gunningham et al. found no significant Selleckchem SC79 up-regulation of VEGF-C in neoplastic tissue compared with normal kidney [2]. According to Leppert

et al., there was no difference in the expression of VEGF-C among three main types of RCC, although its main receptor VEGF-R3 was overexpressed in CCRCC [22]. Also, a reduction of mRNA VEGF-C in tumors was observed; however, it was not biologically significant [2]. Recent results reported by Iwata et al. [10] showed no significant relationship between VEGF-C expression and clinicopathologic features Quisinostat in vivo of RCC, while we found diffuse cytoplasmic and perimembranous distribution to be associated with different clinicopathologic

parameters. Moreover, survival analysis showed a significantly shorter overall survival in patients with tumors exhibiting high diffuse cytoplasmic staining of VEGF-A/C. This controversial but statistically consistent result may suggest that detection of the cytoplasmic pattern in immunohistochemical distribution of VEGF-C could possible mean activation of various mechanisms in the progression of CCRCC. Regarding HIF-1α expression in normal renal parenchyma, there was no positive reaction in glomeruli and no nuclear positivity in normal tubular epithelium, as reported by Di Cristofano et al. [23]. In CCRCC, the expression was nuclear and/or cytoplasmic ranging from low to strong intensity. Some authors report on protein expression of HIF-1α in the tissue of RCC to be significantly higher than in renal parenchyma adjacent to the cancer [24]. The present study demonstrated correlation of overexpression of all three proteins analyzed, i.e. HIF-1α, VEGF-A and VEGF-C. Both nuclear and diffuse cytoplasmic positivity was statistically important in comparison with angiogenic factor expression and clinicopathologic parameters.

Nuclear HIF-1α expression was associated with better prognosis in CCRCC, while cHIF-1α was related to worse prognostic factors and shorter patient survival. Recent literature data on the expression of this regulatory isothipendyl factor are still controversial. According to Kubis et al., up-regulation of the angiogenic genes is due to an increase of HIF-1α protein levels in the cytoplasm by inhibition of its targeting for proteosomal degradation and not by regulation of nuclear import by its nuclear location signal [25]. Lindgren et al. did not evaluate nuclear staining and found the cHIF-1α levels in patients with CCRCC to be significantly lower in locally aggressive tumors than in localized tumors [26]. Klatte et al. conclude that high nHIF-1α expression significantly correlates with markers of apoptosis, VEGFs, and worse survival as compared with patients with low nuclear expression, which was demonstrated by multivariate analysis [24]. Di Cristofano et al.