Abstract
BackgroundProstaglandin (PG) F2α is a key regulator of endometrial function and exerts its biological action after coupling with its heptahelical G protein-coupled receptor (FP receptor). In endometrial adenocarcinoma the FP receptor expression is elevated. We have shown previously that PGF2α-FP receptor signalling in endometrial adenocarcinoma cells can upregulate several angiogenic factors including fibroblast growth factor-2 (FGF2). In the present study, we investigated the paracrine effect of conditioned medium produced via PGF2α-FP receptor signalling in endometrial adenocarcinoma cells stably expressing the FP receptor (Ishikawa FPS cells), on endothelial cell function.ResultsConditioned medium (CM) was collected from FPS cells after 24 hrs treatment with either vehicle (V CM) or 100 nM PGF2α (P CM). Treatment of human umbilical vein endothelial cells (HUVECs) with P CM significantly enhanced endothelial cell differentiation (network formation) and proliferation. Using chemical inhibitors of intracellular signalling, we found that P CM-stimulated endothelial cell network formation was mediated by secretion of endothelial PGF2α and activation of endothelial FP receptors, following FGF2-FGFR1 signalling, phosphorylation of ERK1/2 and induction of COX-2. Whereas, P CM stimulation of endothelial cell proliferation occurred independently of PGF2α secretion via an FGF2-FGFR1-ERK1/2 dependent mechanism involving activation of the mTOR pathway.ConclusionsTaken together, we have shown a novel mechanism whereby epithelial prostaglandin F2α-FP signalling regulates endothelial cell network formation and proliferation. In addition we provide novel in vitro evidence to suggest that prostaglandin F2α can directly regulate endothelial cell network formation but not endothelial cell proliferation. These findings have relevance for pathologies where the FP receptor is aberrantly expressed, such as endometrial adenocarcinoma, and provide in vitro evidence to suggest that targeting the FP receptor could provide an anti-angiogenic approach to reducing tumour vasculature and growth.
Highlights
Prostaglandin (PG) F2a is a key regulator of endometrial function and exerts its biological action after coupling with its heptahelical G protein-coupled receptor (FP receptor)
We found that F-prostaglandin receptor (FP) receptor, fibroblast growth factor-2 (FGF2) and FGF2 receptor 1 (FGFR1) co-localised within the vascular endothelial cells in endometrial adenocarcinomas suggesting that PGF2a may directly and indirectly regulate endothelial cell function [12]
To determine if the effects of PGF2a-FP receptor interaction in endometrial adenocarcinoma cells on endothelial cell function were mediated by FGF2, we used conditioned medium (CM) from Ishikawa FPS cells treated with vehicle or 100 nM PGF2a for 24 hours
Summary
Prostaglandin (PG) F2a is a key regulator of endometrial function and exerts its biological action after coupling with its heptahelical G protein-coupled receptor (FP receptor). Data generated in our laboratory and others have ascertained a role for the cyclooxygenase (COX)-prostaglandin (PG) axis in the regulation of endometrial adenocarcinomas by increasing cell proliferation and the secretion of angiogenic growth factors [4,5] This is similar to other cancers where over-expression of COX enzymes and biosynthesis of prostaglandins has been shown to promote cellular proliferation [6], inhibit apoptosis [7] and enhance angiogenesis [8]. The proposed mechanism of angiogenesis suggests that tumour cells secrete stimulatory factors which act in a paracrine manner on surrounding blood vessels, immune cells and fibroblasts to promote the proliferation, differentiation and migration of endothelial cells towards the stimulus [10,11]. In human endometrial adenocarcinomas VEGF-A and FGF2 expression and secretion are elevated [12,13,14] and both VEGF-A and FGF2 can stimulate angiogenesis in xenografts in vivo [15,16]
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