Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis.

Membrane arachidonic acid is converted by cyclooxygenase (COX) into prostaglandin (PG) G(2) and then to PGH(2) which is subsequently metabolized to PGE(2) by PGE synthase (PGES). Both COX-1 and COX-2 play critical roles in intestinal polyp formation, whereas COX-2 is also expressed in cancers of a variety of organs. Likewise, inducible microsomal PGES (mPGES-1) is expressed in several types of cancer, although its role in benign polyp formation has not been investigated. We demonstrated recently that most COX-2-expressing cells in the polyps are stromal fibroblasts. Here we show colocalization of COX-1, COX-2 and mPGES in the intestinal polyp stromal fibroblasts of Apc(Delta 716) mice, a model for familial adenomatous polyposis. Contrary to COX-2 that was induced only in polyps >1 mm in diameter, COX-1 was found in polyps of any size. In polyps >1 mm, not only COX-2 but also mPGES was induced in the stromal fibroblasts where COX-1 had already been expressed. Although polyp number and size were markedly reduced in COX-1 (-/-) or COX-2 (-/-) compound mutant Apc mice, both COX-2 and mPGES were induced in the COX-1 (-/-) polyps, whereas COX-1 was expressed in the COX-2 (-/-) polyps. We found also in human familial adenomatous polyposis polyps that COX-2 and mPGES were induced in the COX-1-expressing fibroblasts. On the basis of these results, we propose that COX-1 expression in the stromal cells secures the basal level of PGE(2) that can support polyp growth to approximately 1 mm, and that simultaneous inductions of COX-2 and mPGES support the polyp expansion beyond approximately 1 mm by boosting the stromal PGE(2) production.