The Role of Inflammatory Cytokines in Ovarian Cells During the Malignant Transformation of Endometriosis

Endometriosis is a chronic estrogen-dependent inflammatory disease characterized by the presence of ectopic endometrial tissue outside the uterus. Inflammation, angiogenesis, immune regulation, and hormonal signaling pathways play complex roles in its pathogenesis, and these microenvironmental factors are believed to contribute to malignant transformation. Particularly, clinical and molecular data support that endometrioid and clear cell epithelial ovarian cancers (EAOC) can originate from endometriotic lesions. Our central hypothesis is that estrogen and pro-inflammatory cytokines (IL-6, IL-1β, VEGF, EGF, IL-10) within the endometriotic microenvironment facilitate malignant transformation by enhancing proliferation, angiogenesis, and intracellular signaling in ovarian cancer cells. To investigate this, Ishikawa endometrial cells were treated with estrogen and cytokines for 48 hours to create an endometriosis-like microenvironment, which was subsequently applied to OVCAR3 ovarian cancer cells. Cell viability was assessed using the MTT assay, and levels of VEGF (Vascular Endothelial Growth Factor), NGF (Nerve Growth Factor), and PI3K (Phosphatidylinositol 3-Kinase) were quantitatively measured via ELISA. Results showed a significant 2–3 fold increase in cell viability and proliferation in both Ishikawa and OVCAR3 cells following combined treatment with cytokines and estrogen (****p < 0.001). Our model recapitulates key biological processes underlying the malignant transformation of endometriosis. Furthermore, the study contributes to the literature by revealing the influence of microenvironmental factors in the transition from endometriosis to ovarian cancer. In conclusion, this study demonstrates the potential role of an estrogen and cytokine-driven endometriotic microenvironment in malignant transformation, highlighting molecular and cellular targets relevant to EAOC development. These findings suggest that this model could be applied to future studies using primary human cells and provide a foundation for developing translational experimental systems with clinical relevance.