Molecular determinants of the response to therapy in ovarian cancer

• Main Author: Ricci, Francesca
• Published: Open University 2013
• Subjects: 616.99465
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590820

Epithelial ovarian cancer (EOC) has the highest mortality rate in the western world among gynecological malignancies. Approximately 70% of patients achieve complete remission after first-line platinum-based therapy, but, unfortunately, almost all patients relapse with resistant disease. Progress has been made in identifying "hallmarks" of cancer, and the presence of cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) have been associated with aggressiveness and chemoresistant properties. The studies reported here were designed to identify a CSC population, and enhance understanding of the role of EMT in the development of drug resistance in ovarian cancer. The expression of sternness markers, in particular the Side Population phenotype, CD133 and ALDH (aldehyde dehydrogenase), were investigated in ovarian cancer cell lines and in human tumors. Unfortunately, in vivo tumorigenic assays demonstrated that none of these markers could be associated with a CSC. On the other hand, I was able to isolate sphere cultures from fresh human turnors, that were highly tumorigenic in nude mice, and more resistant to drugs currently used in therapy (suggesting a role for these cells in drug resistance), and expressed mesenohymal markers, reinforcing the concept of connection between CSCs and EMT. I obtained ovarian cancer xenografts that mimicked their original human tumors ,and characterized them for sensitivity to cisplatin (DDP) by treating mice with two DDP cycles, mimicking the clinic. On the basis of the response to DDP, xenografts were classified as "Responders" and "Non-Responders". Studies performed to clarify the mechanisms at the basis of the different sensitivity showed that some EMT genes were more highly expressed in cisplatin-"Non-Responder" than in "Responder" xenografts. These data have to be validated in a wider panel of xenografis, in human turnors, and could hopefully defme if EMT markers could be considered predictive of the response to therapy in ovarian cancer.