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 recognized as a primary response gene thought to be involved in modulating cell proliferation and differentiation. To further characterize the role of the cyclooxygenases in cell proliferation, differentiation, and tumorigenicity we developed embryonic stem (ES) cell lines which contain homozygous disruptions 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 potential. Our results demonstrate that the wild-type ES cells do not express either 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 that 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-type cells by exhibiting greater keratinization in the areas of squamous epithelium and the ossification of bone-forming cartilage. We conclude that the presence of a functional COX-2 enzyme is necessary for the efficient growth of these teratocarcinomas in animals.
Zhang
X
X
E. Henry Keutmann Laboratory, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Morham
S G
SG
Langenbach
R
R
Baggs
R B
RB
Young
D A
DA
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005838:Genotype; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D018243:Teratocarcinoma / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D014185:Transplantation, Isogeneic
D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse