Journal Article

The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC<sup>Δ474</sup> knockout mice

Ken-ichi Sunayama, Hiroyuki Konno, Toshio Nakamura, Hidehumi Kashiwabara, Tsuyoshi Shoji, Toshihiro Tsuneyoshi and Satoshi Nakamura

in Carcinogenesis

Volume 23, issue 8, pages 1351-1359
Published in print August 2002 | ISSN: 0143-3334
Published online August 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.8.1351
The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APCΔ474 knockout mice

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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 APCΔ474 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.

Keywords: APC, adenomatous polyposis coli; PCNA, proliferating cell nuclear antigen; TUNEL, TdT-mediated dUTP nick end labeling

Journal Article.  5396 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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