The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APCΔ474 knockout mice

Abstract

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.

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

“…The increased expression of COX-2 in MDF is mostly due to stromal cells. Accordingly, we also found that macrophages (CD-68 positive cells) were present in the stroma pertaining to MDF, suggesting, as reported by others, 25,37,38 that these cells could contribute to COX-2 activity during colon carcinogenesis. Macrophage infiltration higher than that in normal mucosa was also found in tumours, but not in ACF.…”

Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc +/min mice

“…Comparing systemic VEGF-A inhibition by Mab G6-31 to genetic deletion of VEGF-A in the intestinal epithelial compartment suggests that, in addition to epithelial cells, other cellular sources of VEGF-A play an important role in Apc ϩ/min adenoma growth. These additional sources of VEGF-A potentially include mononuclear cells (34) and stromal fibroblasts (35,36). Our in situ analysis indicates extraepithelial VEGF-A expression within the adenomas and normal villi, supporting this notion.…”

JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

“…14,15 This compound also inhibited liver and lung metastases of colon cancer expressing COX-2 but lacked effect on those lacking COX-2 expression in the nude mouse xenograft model. 16,17 In chemically induced colon carcinogenesis, we have previously shown that JTE-522 inhibited the development of aberrant crypt foci (ACF), the putative precursors of both human and experimental colon cancer, 18,19 when administered throughout the study.…”