The
prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of
prostaglandin (PG) E(2).
PTGS2 expression and
PGE(2) biosynthesis is elevated in endometrial
adenocarcinoma, however the mechanism whereby PTGS and
PGE(2) regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the
PGE synthase
enzymes (PTGES, PTGES-2, PTGES-3) and
PGE receptors (PTGER1-4) in endometrial
adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial
tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial
adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial
adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4
cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of
PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and
hypoxia. In vitro, we found that
PGE(2) and
hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating
prostanoid receptor expression. Finally we have shown that
PGE(2) and
hypoxia synergise to promote cellular proliferation of endometrial
adenocarcinoma cells.