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Cyclooxygenase 2- and Prostaglandin E₂ Receptor EP₂-dependent Angiogenesis in Apc⁷¹⁶ 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 (Apc⁷¹⁶) 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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