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(Delta474) 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 microm in diameter) which lacked normal villous structure, and small
adenomas (</=300 microm) 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.