RT Journal Article
SR Electronic
T1 Cooperation of Cyclooxygenase 1 and Cyclooxygenase 2 in Intestinal Polyposis
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4872
OP 4877
VO 63
IS 16
A1 Takeda, Haruna
A1 Sonoshita, Masahiro
A1 Oshima, Hiroko
A1 Sugihara, Ken-ichi
A1 Chulada, Patricia C.
A1 Langenbach, Robert
A1 Oshima, Masanobu
A1 Taketo, Makoto M.
YR 2003
UL http://cancerres.aacrjournals.org/content/63/16/4872.abstract
AB Membrane arachidonic acid is converted by cyclooxygenase (COX) into prostaglandin (PG) G2 and then to PGH2 which is subsequently metabolized to PGE2 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 ApcΔ716 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 PGE2 that can support polyp growth to ∼1 mm, and that simultaneous inductions of COX-2 and mPGES support the polyp expansion beyond ∼1 mm by boosting the stromal PGE2 production. ©2003 American Association for Cancer Research.