Analysis of p53 and vascular endothelial growth factor and its receptor Flk-1 expression in human gallbladder carcinoma for determination of tumor vascularity

Abstract

Objective: More and more studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. There is some evidence that p53 mutations cause overexpression of vascular endothelial growth factor (VEGF), a major inducer of angiogenesis. In addition, there is now growing evidence that several malignancies express receptors for VEGF, especially receptor-2 (Flk-1/KDR), raising the possibility that the VEGF/VEGF receptor axis may serve as an autocrine pathway in some tumors. We examined the expression of p53 and VEGF and its receptor FlK-1, together with microvessel count (MVC) to investigate the role of VEGF as an angiogenic marker, the presence of VEGF/Flk-1 axis, and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma. Methods: Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, Flk-1 and factor VIII-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage, differentiation grade, MVC, and lymph nodes metastasis. Results: VEGF, Flk-1 expression and positive p53 protein accumulation and BEGF expression was found in 63.3%, 67.3% and 61.2% of tumors, respectively. The expression of Flk-1 was markedly correlated with VEGF (P<0.05). The percentage of the patients with both positive VEGF and Flk-1 expressions was 49.0% (24/49), and their MVC value was markedly higher than that of the others. P53 and VEGF staining status were identical in 55.1% of tumors. The Nevin staging of p53-or VEGF-positive tumors was significantly later than negative tumors. The MVC in p53-or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups. Conclusion: The findings suggest the VEGF/Flk-1 axis and p53-VEGF pathway tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression, plus Flk-1 and VEGF expression might be useful for predicting the tumor vacularity and biologic behaviors of gallbladder cancer.