ABSTRACT
Ectopic pregnancy (EP) is defined as the implantation of an embryo outside of the uterus and is a leading cause of first trimester maternal mortality and morbidity. This article discusses a possible role for epithelial to mesenchymal transition in the pathogenesis of EP, given the notable similarity of protein expression between the two processes.
Subject(s)
Epithelial-Mesenchymal Transition , Pregnancy, Ectopic , Embryo Implantation , Female , Humans , Pregnancy , Pregnancy Trimester, First , Pregnancy, Ectopic/etiology , UterusABSTRACT
1-2% of pregnancies are ectopic, the majority implanting in the Fallopian tube. A single, systemic dose of methotrexate, a DNA-synthesis (S phase) inhibitor, has been used since 1991 for outpatient treatment of women with stable EP. However, methotrexate has limited clinical and cost effectiveness, restricting its use to 25-30% of these women. There is an unmet need for better medical treatment for EP. Colony stimulating factor-1 (CSF-1) promotes placentation and creates a pro-inflammatory environment that is fundamental for the maintenance of a normal pregnancy. We hypothesised that CSF-1 is also involved in the placentation and maintenance of an EP. Herein, we demonstrate the immunolocalisation of the CSF-1 receptor (CSF-1R) as well as its ligand (CSF-1) in immortalised first trimester trophoblast cells. We show that a specific CSF-1R kinase inhibitor, GW2580, abolishes CSF-1 induced trophoblast cell proliferation and migration and can be cytotoxic. We then demonstrate the expression of CSF-1R and CSF-1 in the cytotrophoblast and syncytiotrophoblast within ectopic implantation sites from women with EP. Our data suggests that CSF-1 is involved in the survival and proliferation of trophoblast cells in EP. This suggests that pharmacological disruption of CSF-1/CSF-1R signaling axis could be the basis of a new therapeutic for EP.
Subject(s)
Molecular Targeted Therapy , Pregnancy, Ectopic/drug therapy , Pregnancy, Ectopic/pathology , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction/drug effects , Cell Death/drug effects , Cell Line , Cell Movement/drug effects , Female , Gene Expression Regulation/drug effects , Humans , Macrophage Colony-Stimulating Factor/metabolism , Pregnancy , Pregnancy, Ectopic/metabolism , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Trophoblasts/drug effects , Trophoblasts/pathologyABSTRACT
Tubal ectopic pregnancies are a leading cause of global maternal morbidity and mortality. Previous infection with Chlamydia trachomatis is a major risk factor for tubal embryo implantation but the biological mechanism behind this association is unclear. Successful intra-uterine embryo implantation is associated with increased expression of endometrial "receptivity" integrins (cell adhesion molecules). We examined integrin expression in Fallopian tubes of women with previous C. trachomatis infection, in mice experimentally infected with C. trachomatis, in immortalised human oviductal epithelial cells (OE-E6/E7) and in an in vitro model of human embryo attachment (trophoblast spheroid-OE-E6/7 cell co-culture). Previous exposure with C. trachomatis increased Fallopian tube/oviduct integrin-subunit beta-1 (ITGB1) in women and mice compared to controls. C. trachomatis increased OE-E6/E7 cell ITGB1 expression and promoted trophoblast attachment to OE-E6/E7 cells which was negated by anti-ITGB1-antibody. We demonstrate that infection with C. trachomatis increases tubal ITGB1 expression, predisposing to tubal embryo attachment and ectopic pregnancy.