Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma.
OBJECTIVE
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 immunohistochemical methods. Microvessel counts (MVC) were determined using CD(34). The relationships between COX-2, VEGF expression, CD(34)-stained MVC, clinicopathologic features and survival time were analyzed. The correlations between COX-2 and VEGF expression, CD(34)-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 S(4)-S(5) (81.8%) than in those of Nevin stages S(1)-S(3) (50.0%) with a statistical significance (P<0.01, 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).


CONCLUSIONS
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.
Zhi
Ying-Hui
YH
Department of General Surgery, Affiliated Beijing Tiantan Hospital, Capital University of Medical Sciences, Beijing 100050, China. yinghuizhi@yahoo.com.cn
Liu
Ruo-Shan
RS
Song
Mao-Min
MM
Tian
Yu
Y
Long
Jin
J
Tu
Wei
W
Guo
Ren-Xuan
RX
D000328:Adult; D051546:Cyclooxygenase 2; D005260:Female; D005706:Gallbladder Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases