Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma

AIM: To investigate the relationships between the expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and the degree of vascularization, clinicopathologic feature, survival time of patients with gallbladder carcinomas. METHODS: Sixty-four gallbladder carcinoma specimens were evaluated for COX-2, VEGF expression by immunohi stochemical methods. Microvessel counts (MVC) were determined using CD34. The relationships between COX-2, VEGF expression, CD34-stained MVC, clinicopathologic features and survival time were analyzed. The correlations between COX-2 and VEGF expression, CD34-stained MVC were also investigated. RESULTS: COX-2, VEGF immunoreactivity were observed in 71.9% (46/64) and 54.7% (35/64) specimens, respectively. The average MVC in 64 cases of gallbladder carcinoma was 57±14 per high power vision field. The status of MVC was closely correlated with Nevin staging, tumor differentiation and lymph node metastasis (P<0.01, 0.002, and 0.003, 0.000, respectively). Increased VEGF expression was significantly correlated with tumor differentiation (poorly and moderately>well differentiated, P<0.05, P = 0.016). Clinical stages had no relation with the expression of VEGF (P>0.05, P = 0.612). There was a positive correlation between COX-2 expression and clinical stages. The positive rate of COX-2 was higher in cases of Nevin stages S4-S5 (81.8%) than in those of Nevin stages S1-S3 (50.0%) with a statistical significance (P0.01, P = 0.009). The expression of COX-2 did not vary with differentiation (P>0.05, P= 0.067). Statistically significant differences were also observed according to lymph node metastasis, COX-2 expression and VEGF expression (P<0.01,0.000, and 0.001, respectively). There was no relation between VEGF, COX-2 expression, MVC and the age and sex of patients. MVC and VEGF positive rate in the COX-2 positive gallbladder carcinoma tissue was higher than that in the COX-2 negative tissue (P<0.05, 0.000, and 0.032, respectively). Patients with VEGF, COX-2 positive tumors had a significantly shorter survival time than those with negative tumors (P<0.05,0.004, 0.01, respectively). CONCLUSION: Augmented tumor neovascularization induced by VEGF may be one of the several effects of COX-2 responsible for poor prognosis of human gallbladder carcinoma. COX-2 inhibitor, either in combination therapy with other agents, or for chemoprevention, may be effective via suppression of angiogenesis in this fatal disease.

Correlation of P-glycoprotein expression with poor vascularization in human gallbladder carcinomas

AIM: To investigate the relationship between the expression of P-glycoprotein (P-gp) and the degree of vascularization in gallbladder carcinomas.METHODS: P-gp was stained with streptavidin-peroxidase complex immunohistochemical method in routine paraffinembedded sections of gallbladder carcinomas. Microvessel counts (MVC) were determined using factor-Ⅷ-related antigens.RESULTS: The average MVC in 32 cases of gallbladder carcinomas was (34±10)/HP. The value of MVC was closely correlated with Nevin staging and tumor differentiation (P＜0.01 and P＜0.05). The total expression rate of P-gp was 62.5 %. The P-gp expression rate in cases of Nevin staging S1-S3 (78.6 %) was higher than that of S4-S5 (50.0 %) with no statistical significance. The P-gp expression rate was not correlated with tumor differentiation or pathologic types. The value of MVC in P-gp (+) cases was markedly lower than that in P-gp (-) cases (P＜0.01). The positive rate of P-gp was significantly higher in cases of smaller MVC than those of bigger MVC (P＜0.05).CONCLUSION: MVC may be used as one of the important parameters to reflect the biological behaviors of gallbladder carcinomas. As a major cause of drug resistance, the overexpression of P-gp is closely correlated with the poor vascularization in gallbladder carcinomas.