The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

Laboratory of Immunology, Paris Descartes University, Hospital Cochin, Paris, France.
American Journal Of Pathology (Impact Factor: 4.59). 06/2011; 179(2):880-9. DOI: 10.1016/j.ajpath.2011.04.020
Source: PubMed


Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.

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Available from: Mahaut Leconte
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    • "Oestrogen-induced ROS play important roles in cell proliferation, migration, invasion and cell transformation, by increasing genomic instability and by transducing signal through redox sensitive transcription factors (Okoh et al., 2011). Various sources of evidence support the role of oxidants in the development of endometriosis, a metastatic benign pathology (Borghese et al., 2010), as endometriotic cells show higher endogenous oxidative stress with increased ROS production and alterations in ROS detoxification pathways (Ngo et al., 2009; Leconte et al., 2011). However, despite evidence that oxidative stress may play a role in endometriosis (Agarwal et al., 2005), to date no study has explored the peritoneal fluid protein oxidative status. "
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    • "Only patients with complete surgical exploration of the abdominopelvic cavity have been included in our series; (ii) all patients underwent a preoperative protocol work-up including TVUS during the month preceding the surgery. All scans were performed by a single experienced radiologist (AEM); (iii) only women with histologically proven uterine leiomyomas were allocated in the leiomyoma group; (iv) for the homogeneity of the study, the control group only included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma; (v) because endometriotic cells display a high endogenous oxidative stress with an increase in ROS production and alterations in ROS detoxification pathways [15,16], women with endometriosis were not included in the study; (vi) although some studies have suggested the relationship between oxidative stress and uterine leiomyoma [22–25], none of these studies have focused on the oxidative status in sera from women with leiomyoma. "
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