Introduction: An ectopic pregnancy (EP) is defined as a conceptus implanting outside of the uterine cavity, most commonly in the Fallopian tube. It is a life-threatening gynaecological condition with limited treatment options. Large and unstable EP are managed by surgical excision. Smaller stable EP are medically managed with the chemotherapeutic drug methotrexate. Methotrexate has considerable side effects and a high treatment failure rate (~30%). There is an unmet medical need for better-tolerated and more efficacious medical treatments for EP. In-vitro studies, data from knockout mice, and human ex-vivo studies suggest that colony-stimulating factor-1 (CSF-1) is essential for the survival of an early pregnancy. We hypothesise targeting CSF-1 receptor signalling may provide a novel therapeutic target for the medical treatment of EP.
Methods: CSF-1R expression was examined in tubal implantation site biopsies obtained from women undergoing surgery for EP (n=4) and in an immortalised human first trimester trophoblast cell line (SW.71) by immunohistochemistry and immunocytochemistry. SW.71 cells were exposed to CSF-1 and a CSF-1R antagonist (GW2580) (with and without CSF-1) at different time points (24 and 48 hours) and at a range of concentrations. Proliferation was measured using an MTT assay.
Results and discussion: CSF-1R was expressed abundantly in the syncytiotrophoblast and cytotrophoblast at tubal implantation sites from women with EP. CSF-1R was also expressed in the SW.71 cells. Exogenous CSF-1 (100 ng/ml) increased proliferation of SW.71 cells (P<0.0001). GW2580 decreased proliferation of SW.71 cells at concentrations 10, 20 and 40 μM after 48 h (P<0.01, P<0.0001, P<0.0001 respectively). GW2580 also decreased proliferation in SW.71 cells with prior exposure to CSF-1 at 20 and 40 μM after 48 h (both P<0.0001).
Conclusion: CSF-1R is expressed in trophoblast cell populations at tubal EP implantation sites. Antagonism of CSF-1 decreases trophoblast cell proliferation. This supports the potential to target CSF-1R signalling as a therapy for EP.
11 Jul 2016 - 11 Jul 2016