Lack of cyclooxygenase-2 inhibits growth of teratocarcinomas in mice

Two isoforms of cyclooxygenase (COX-1 or COX-2) have been identified in the prostanoid biosynthetic pathway. The constitutive form, COX-1, is thought to maintain cellular homeostasis and the inducible form, COX-2, is recogniz ed as a primary response gene thought to be involved in modulating cell pro liferation and differentiation. To further characterize the role of the cyc looxygenases in cell proliferation, differentiation, and tumorigenicity we developed embryonic stem (ES) cell lines which contain homozygous disruptio ns in either the COX-1 or the COX-2 gene. These lines were then examined in terms of their viability, proliferation, and in vitro differentiation pote ntial. Our results demonstrate that the wild-type ES cells do not express e ither COX-1 or COX-2 until the cells undergo differentiation. And the lack of either cyclooxygenase has no apparent effect on ES cell proliferation in vitro, However, the absence of a functional COX-2 gene leads to a dramatic reduction in the formation and growth of teratocarcinomas that appear when ES cells are injected into syngeneic mice. Histological microscopy shows t hat the few very small tumors that were generated from ES cells lacking COX -2 appear more differentiated than tumors emerging from COX-1 -/- or wild-t ype cells by exhibiting greater keratinization in the areas of squamous epi thelium and the ossification of bone-forming cartilage. We conclude that th e presence of a functional COX-2 enzyme is necessary for the efficient grow th of these teratocarcinomas in animals. (C) 2000 Academic Press.