Intercellular Transfer of microRNAs in Epithelial Ovarian Cancer

Epithelial ovarian cancer is a leading cause of death from gynecological malignancies. A lot of the roadblocks in effectively treating patients with metastatic disease and preventing chemo-resistance can be attributed to the insufficient understanding of the biology and the mechanisms involved in ovarian cancer metastasis. The tumor microenvironment is a heterogeneous system, characterized by complex interactions between different cell types, which are mediated by several means of cell-to-cell communication. A recently discovered mechanism of intercellular communication is the cell-to-cell transfer of microRNAs. MicroRNAs and their role in cancer have attracted a lot of attention in recent years. They have been identified as key regulators of metastatic progression, tumor response to treatments, and clinical outcomes in ovarian cancer. As the transfer of functional microRNAs between cells could lead to dramatic changes in the fate of the cell-recipient, this dissertation explores their role as mediators of intercellular communication in the ovarian cancer microenvironment. Using time-lapse confocal microscopy, multi-photon imaging and flow cytometry the process of microRNA transfer between the cells was visualized and its magnitude quantified. Functional intercellular transfer of microRNA-200a was demonstrated across both natural as well as artificial gradients of expression levels. The microRNA-200 family is a versatile player in ovarian cancer and has been shown to play an important role in epithelial to mesenchymal transition and metastasis. A double negative feedback loop between miR-200 and the ZEB genes taken into context along with the potentially functional transfer of the microRNA between the cells could further the understanding of the reversible EMT process. This project thus aims to characterize intercellular microRNA transfer and its functional significance in epithelial ovarian carcinoma.