Carcinogenesis, Vol. 23, No. 8, 1351-1359,
August 2002
© 2002 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC
474 knockout mice
1 2nd Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan and
2 Department of Materials Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi-Shi, Shizuoka, 437-8555, Japan
The expression of COX-2 participates strongly in polyp formation of adenomatous polyposis coli (APC)-mutated mice. However, the mechanism of growth inhibition by COX-2 inhibition remains unclear. The aims of this study were to assess the role of COX-2 during the process of polyp formation in APC
474 knockout mice. Starting at 4 weeks of age, the treated group (T group) were given a diet containing JTE-522, a selective COX-2 inhibitor, and the control group (C group) were given a control diet. At 12 weeks of age, mice were killed and polyps located in a proximal 10 cm of the small intestine were classified into two morphological stages: large adenomas (>300 µm in diameter) which lacked normal villous structure, and small adenomas (
300 µm) covered with normal villous epithelia. In both classes, after counting the incidence, adenomas were examined for vascularity, expression of COX-2 and VEGF protein, labeling proliferating cell nuclear antigen (PCNA) and apoptosis with the TdT-mediated dUTP nick end labeling method, including expression of Bcl-2 and Bcl-X. JTE-522 significantly reduced the incidence of large adenomas, but not of small adenomas. Although it did not affect the proliferating potential of adenomas, the apoptosis index increased significantly in the T group accompanied by a reduction in Bcl-X expression in both small and large adenomas. In the C group, macrophages with both COX-2 and VEGF expression were observed in the submucosa of large adenomas, where some large vessels were also observed. JTE-522 inhibited the VEGF expression of these macrophages, resulting in a decrease in vascular area. In conclusion, macrophages with COX-2 and VEGF expression in the submucosal layer are responsible for angiogenesis in large adenomas, and a selective COX-2 inhibitor reduced the growth of adenoma mainly by its inhibitory effect on angiogenesis.
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