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Molecular Biology and Genetics |
716 Mouse Intestinal Polyps1
Departments of Pharmacology [H. S., M. O., T. I., H. O., K. T., S. N., M. M. T.] and Gastroenterology and Hepatology [H. S., T. C.], Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
To investigate angiogenesis during intestinal polyp development, we determined the microvessel density (MVD) in polyps of Apc knockout (Apc
716) mice, a model for human familial adenomatous polyposis. We scored MVD also in several compound mutants carrying Apc716, namely, mice with an additional mutation in Smad4, in which the polyps progress into invasive adenocarcinomas; mice with a cyclooxygenase (COX)-2 gene (Ptgs2) mutation, in which adenoma growth is suppressed; and mice with prostaglandin E2 EP receptor gene mutations. In both simple Apc716 and compound Apc716 Smad4 mutants, MVD increased in a polyp size-dependent manner only in the polyps expanded beyond a threshold of about 1 mm in diameter. These results indicate that tumor angiogenesis is stimulated only after tumors grow to a certain size, and this angiogenic switch is common to both benign adenomas and malignant adenocarcinomas. In Apc716 polyposis attenuated by the COX-2 gene mutation, in contrast, MVD did not increase even in polyps larger than 1 mm. The same phenomenon was observed in the compound mutant mice with Apc716 and the EP2 receptor gene mutations, but not in other EP compound mutants. We also immunohistochemically studied COX-2 and angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor. Interestingly, expression of these proteins was also increased in polyps larger than 1 mm. These results suggest that, in both benign and malignant mouse intestinal tumors, stromal expression of COX-2 results in elevated prostaglandin E2 levels that stimulate cell surface receptor EP2, followed by induction of vascular endothelial growth factor that causes tumor angiogenesis.
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M. Sonoshita, K. Takaku, M. Oshima, K.-i. Sugihara, and M. M. Taketo Cyclooxygenase-2 Expression in Fibroblasts and Endothelial Cells of Intestinal Polyps Cancer Res., December 1, 2002; 62(23): 6846 - 6849. [Abstract] [Full Text] [PDF]
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