ABSTRACT
Endometriosis is one of the most common gynecological and systemic diseases, with a remarkable immune background. Patients suffer from pain and fertility reduction. Due to the distinct immune component, an immunotherapeutic approach may gain importance in the future. In endometriosis, shifts in the cell fractions of the immune system are well known. Moreover, hypoxia concomitant with inflammation causes a disturbed immune response. The removal of endometriosis has a therapeutic effect, normalizes the immune disorders, and remains the most effective causative treatment in terms of pain and infertility. A key issue is whether a similar effect can be achieved for fertility with non-invasive immunotherapy where surgery is inadvisable or cannot be performed for various reasons. Numerous immunotherapy trials, including vaccines, were conducted on animals only, although the research is encouraging. Among the promising methods of non-specific immunotherapy is the administration of an ethiodized oil contrast. Moreover, due to the significant successes of immunotherapy in oncology, the possibility of immunotherapy affecting NK cells has been postulated. NK cells are responsible for the surveillance and apoptosis of ectopic cells. Expanding the arsenal of endometriosis treatment by immunotherapy is promising due to the significant contribution of immunological factors and the limitations of current treatment methods.
ABSTRACT
Granulosa cell tumors (GCT) of the ovary have a good prognosis. Recurrence tends to be late; however, > 66 % of patients with recurrent GCT die from the disease. Most recurrences are abdominopelvic, although distant metastases have been documented. Here, we tested the hypothesis that a mixture of persistent endocrine-disrupting chemicals (EDCs) stimulates the invasion of GCT cells. We selected perfluorooctanoate (PFOA, 2 ng/mL), perfluorooctanesulfonate (PFOS, 8 ng/mL), 2,2-dichlorodiphenyldichloroethylene (p,p'-DDE, 1 ng/mL), polychlorinated biphenyl 153 (PCB153, 100 pg/mL), and hexachlorobenzene (HCB, 50 pg/mL), which have the highest measured concentrations in follicular fluid of women undergoing treatment with assisted reproductive technology. The human GCT cell lines COV434 and KGN have been used as in vitro models of juvenile (JGCT) and adult (AGCT) GCT subtypes, respectively. Cells were treated with a mixture of the test compounds for 15 min prior to analysis of protein phosphorylation; for 4 h prior to analysis in a circular chemorepellent-induced defect assay; for 6 h prior to analysis of matrix metalloproteinase 2 (MMP2) activity; for 24 h prior to analysis of migration, invasion, and gene expression; and for 48 h prior to analysis of protein expression. First, we showed that KGN cells migrated and exhibited invasive behavior. By contrast, COV434 cells lacked migration and invasion potential. Moreover, expression of mesenchymal genes and the gene encoding MMP2 was higher in KGN cells, and that of epithelial genes lower, than that in COV434 cells. Treatment of KGN cells with the EDC mixture stimulated cell migration, invasion, and lymphatic dissemination. The results suggest that the role of the EDC mixture in AGCT invasion is not related to changes in expression of epithelial and mesenchymal genes; rather, it is related to increased expression and activity of MMP2. Additionally, silencing insulin-like growth factor 1 (IGF1R) in AGCT abolished the stimulatory effect of the EDC mixture on KGN spheroid invasion. These results demonstrate that the EDC mixture increased KGN spheroid invasion by stimulating expression and activity of MMP2 via IGF1R.
