Selective modulation of the prostaglandin F2α pathway markedly impacts on endometriosis progression in a xenograft mouse model

Abstract

Study hypothesis: Selective activation or blockade of the prostaglandin (PG) F2α receptor (FP receptor) affects ectopic endometrial tissue growth and endometriosis development.

Study finding: FP receptor antagonists might represent a promising approach for the treatment of peritoneal endometriosis.

What is know already: Eutopic and ectopic endometrium from women with endometriosis exhibit higher expression of key enzymes involved in the PGF2α biosynthetic pathway. It has also been shown that the PGF2α-FP receptor interaction induces angiogenesis in human endometrial adenocarcinoma.

Study design, samples/materials, methods: For this study, a mouse model of endometriosis was developed by inoculating human endometrial biopsies into the peritoneal cavity of nude mouse (n = 15). Mice were treated with AL8810 (FP receptor antagonist), Fluprostenol (FP receptor agonist) or PBS. Endometriosis-like lesions were collected and analysed for set of markers for angiogenesis, tissue remodelling, apoptosis, cell proliferation and capillary formation using qPCR and immunohistochemistry.

Main results and the role of chance: We found that selective inhibition of the FP receptor with a specific antagonist, AL8810, led to a significant decline in the number (P < 0.01) and size of endometriosis-like lesions (P < 0.001), down-regulated the expression of key mediators of tissue remodelling (MMP9, P < 0.05) and angiogenesis (VEGF, P < 0.01) and up-regulated the pro-apoptotic factor (Bax, P < 0.01) as compared with controls. Immunohistochemical analyses further showed a marked decrease in cell proliferation and capillary formation in endometrial implants from AL8810-treated mice, as determined by proliferating cell nuclear antigen (PCNA) and von Willebrand factor (vWF) immunostaining, respectively. Moreover, Fluprostenol, a selective FP receptor agonist, showed the opposite effects.

Limitations, reasons for caution: We carried out this study in nude mice, which have low levels of endogenous estrogens which may affect the lesion growth. Caution is required when interpreting these results to women.

Wider implications of the findings: This study extends the role of PG signalling in endometriosis pathogenesis and points towards the possible relevance of selective FP receptor antagonism as a targeted treatment for endometriosis.

Large scale data: Not Applicable.

Study funding and competing interests: This work was supported by grant MOP-123259 to the late Dr Ali Akoum from the Canadian Institutes for Health Research. The authors have no conflict of interest.

Keywords: AL8810; FP receptor; Fluprostenol; PGF2α; endometriosis; prostaglandins.