title: Selective modulation of the prostaglandin F2α pathway markedly impacts on endometriosis progression in a xenograft mouse model.
abstract: OBJECTIVE
  Selective activation or blockade of the prostaglandin (PG) F2α receptor (FP receptor) affects ectopic endometrial tissue growth and endometriosis development.
  
  
  RESULTS
  FP receptor antagonists might represent a promising approach for the treatment of peritoneal endometriosis.
  
  
  BACKGROUND
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  METHODS
  Not Applicable.
  
  
  BACKGROUND
  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.
authors.affiliation: Laboratoire d'Endocrinologie de la Reproduction, Centre de recherche, CHU de Québec-HSFA, Faculté de Médecine, Université Laval, Québec, Canada MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK furquan.ahmad@ed.ac.uk.
authors.forename: Syed Furquan
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Laboratoire d'Endocrinologie de la Reproduction, Centre de recherche, CHU de Québec-HSFA, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Akoum
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004715:Endometriosis / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008186:Luteolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C518977:AL 8810 ethylamide; D008186:Luteolytic Agents; D011461:Prostaglandins F, Synthetic; C006326:fluprostenol; D015237:Dinoprost; D015232:Dinoprostone
keywords: AL8810; FP receptor; Fluprostenol; PGF2α; endometriosis; prostaglandins