Ovarian cancer is the leading cause of gynaecological cancer mortality in women, with epithelial ovarian cancer (EOC) being the most common subtype. Poor patient survival is largely attributed to a limited understanding of early developmental processes, concomitant with no early detection diagnostic tools. Previously, we observed that the loss of oocytes from primordial follicles enables the transformation of abandoned somatic pregranulosa cells into heterogeneous ovarian tumours in mice [1, 2]. Herein, we further investigate the role of the oocyte in the development of EOC. Based on our previous findings, we hypothesise that oocyte-secreted factors will suppress EOC disease progression.
Using mouse and human EOC cell lines (mOSET2, T2BR and OVCAR-3), we assessed the impact of cumulus-oocyte-complex (COC)-conditioned media or COC co-cultures on cell proliferation (tritiated thymidine incorporation assay) and gene expression of key markers (via quantitative PCR). Both treatment groups reduced cell proliferation and decreased expression of proliferation-related genes Cdkn1b and Ccne1 in the mOSET2 cell line, and c-KIT in the OVCAR-3 cell line. Oocyte-secreted factors from COC co-cultures also tended to reduce the expression of EOC markers, Cdh1 (E-cadherin), Dab2 and Muc16, in the mouse mOSET2 cells, and CDH1 and MUC16 in the human OVCAR-3 cell line; however, this was not statistically significant. The anti-mitogenic effects and decrease in epithelial gene markers were not observed when cells were treated with denuded oocytes alone, cumulus cells alone, or recombinant exogenous oocyte-specific secreted proteins, GD9 and BMP15. Thus, the factors within the COC conditioned media responsible for this inhibitory effect remain unknown. However, additional investigation is currently underway by RNA sequencing to elucidate the potential molecular mechanisms.
These results support a novel paradigm in which COCs may play a key role in EOC development. This improved mechanistic understanding will have implications for early detection, prevention and therapeutic intervention of this disease.