Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients

Abstract

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

Clinical significance of programmed death‐1 and programmed death‐ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma

“…Receiver operating characteristic curve analysis was undertaken to determine the area under the curve, and the optimal cut-off value was taken as the farthest point from the diagonal line of the curve. 4 Cases in which the PD-1-positive TIIC score, PD-L1-positive TIIC score, or PD-L1positive tumor score was higher than the cut-off values were defined as high cases, and those with percentages lower than the cut-off values were defined as low cases. The log-rank test and Kaplan-Meier method were used for survival analyses.…”

“…Statistical analysis of the ccRCC tissues without pretreatment was carried out by dividing them into the following groups: groups of low stage (pT1 and pT2) and high stage (pT3 and pT4) or groups of low grade (grades 1 and 2) and high grade (grades 3 and 4). Receiver operating characteristic curve analysis was undertaken to determine the area under the curve, and the optimal cut‐off value was taken as the farthest point from the diagonal line of the curve . Cases in which the PD‐1‐positive TIIC score, PD‐L1‐positive TIIC score, or PD‐L1‐positive tumor score was higher than the cut‐off values were defined as high cases, and those with percentages lower than the cut‐off values were defined as low cases.…”

“…Although VEGF‐TKI treatment is considered to be superior to conventional immunotherapy, resistance to therapy is commonly observed in most ccRCC patients treated with VEGF‐TKI within 1 year after treatment . Several molecular mechanisms for resistance are suggested such as the tumor immune escape mechanism, cancer stem cells, epithelial mesenchymal transition, and reactivation of angiogenesis . Among them, the tumor immune escape mechanism is considered to be one of the hallmarks of cancer because cancer cells need to escape from destruction by the immune system to survive …”

“…2 Several molecular mechanisms for resistance are suggested such as the tumor immune escape mechanism, cancer stem cells, epithelial mesenchymal transition, and reactivation of angiogenesis. 1,[3][4][5] Among them, the tumor immune escape mechanism is considered to be one of the hallmarks of cancer because cancer cells need to escape from destruction by the immune system to survive. 6 Programmed death-ligand 1 is known to be expressed by both TIIC in the tumor microenvironment and tumor cells, and it engages PD-1 on T cells, triggering inhibitory signaling of the T-cell receptor, thereby blocking effector functions and reducing T cell killing capacity.…”

Clinical and prognostic role of Vasohibin-1 expression in solid tumors: An evidence from a meta-analysis

“…studies were identified as meeting our inclusion criteria [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], whose detailed information was shown in Table 2. The VASH1 relatively-low expression group (1225 individuals; 52.8%) was regarded as the control group.…”