The prognostic significance of vasohibin 1–associated angiogenesis in patients with hepatocellular carcinoma

Abstract

Vasohibin 1, an endothelium-derived negative feedback regulator of angiogenesis, is induced by fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor A (VEGF-A). In this study, we retrospectively evaluated immunoreactivity of FGF-2 and VEGF-A as well as microvessel density (MVD) determined by expression of vasohibin 1 and CD34 (MVD-CD34) and correlated the findings with clinical outcomes of 181 patients with hepatocellular carcinoma (HCC). Double immunostaining of an endothelial marker CD34 and vasohibin 1 with Ki-67 was also performed to assess angiogenic activity of endothelial cells in HCC. The ratio of Ki-67-positive endothelial cells in vasohibin 1-positive vessels (22%) was significantly higher than that of CD34-positive vessels (9%, P < .001), suggesting the correlation between vasohibin 1 and neovascularization in endothelial cells of HCC. MVD-CD34 decreased, but the ratio of MVD determined by expression of vasohibin 1 to MVD-CD34 (vasohibin 1/CD34) increased significantly according to histologic grade. Vasohibin 1 was significantly correlated with the status of FGF-2 (P = .007) but not with that of VEGF-A (P = .055). The 10-year overall survival and the 2-year disease-free survival rates of the low vasohibin 1/CD34 group (vasohibin 1/CD34 ≤0.459) were significantly higher than those of the high vasohibin 1/CD34 group (vasohibin 1/CD34 >0.459) (survival, 48% versus 38% and 52% versus 35%; P < .001 and P < .05, respectively). In addition, vasohibin 1/CD34 in HCC patients was an independent marker of poor prognosis, as determined by multivariate analysis (risk ratio, 1.973; 95% confidence interval, 1.049-3.711; P = .035). Vasohibin 1/CD34 could identify the proliferative vessels and could be a useful biomarker for predicting the clinical outcome of HCC patients.