Abstract 4091: Investigations on the role of epithelial-mesenchymal transition and cancer stem cells in the response to therapy in patient-derived ovarian carcinoma xenografts
Authors: Ricci Francesca , Guffanti Federica , Fratelli Maddalena , Massimo Broggini , Damia Giovanna 
Published: August 2015

Epithelial ovarian cancer (EOC) has the highest mortality rate in the western world among gynaecological malignancies. Approximately 70% of patients achieve complete remission after first-line platinum-based therapy, but unfortunately, almost all patients relapse with the development of a resistant disease. Progress has been made in identifying “hallmarks” of cancer, and the epithelial-mesenchymal transition (EMT) and the presence of cancer stem cells (CSCs) have been associated with aggressiveness and chemoresistant properties.

These studies were designed to better understand the role of CSCs and EMT in the resistance to a platinum-based therapy in a panel of patient-derived ovarian carcinoma xenografts recently characterized (Ricci F et al, Cancer Res 2014). These xenografts reproduce the complexity and the heterogeneity of ovarian cancer both at a biological (i.e. histotypes, pattern of spread) and molecular levels (i.e. gene mutations and transcriptomic).

In order to investigate the role of EMT and CSC in ovarian cancer, 10 different ovarian carcinoma xenografts (4 serous, 3 endometrioid, 2 mucinous, and 1 müllerian-mixed tumor) were treated with cisplatinum (CDDP) once a week for 3 weeks at the dose of 5 mg/kg. Then, a second CDDP cycle was given to the regrowing tumors, mimicking clinical conditions. Ovarian xenografts showed different sensitivity to the first CDDP cycle, but almost all were less sensitive to the second CDDP cycle. Xenografts were classified as “Very Responsive” (VR), “Responsive” (R), and “Non-Responsive” (NR) on the basis of their therapy response. By RT-PCR (Qiagen, RT2 ProfilerTM PCR Array System) the expression of EMT and CSCs genes (n = 86 for each array) was evaluated in untreated and CDDP-treated xenografts. Statistical analysis were performed by using the Significance of Microarrays (SAM) method.

The expression of EMT genes supported the recently put forward idea that the different ovarian histotypes are to be considered as different diseases. Indeed, xenografts belonging to the same hystotype clustered in the same group. We then focus on the role of EMT genes in prediciting CDDP sensitivity in serous and endometroid carcinomas subtype. We found that transcription factor 3 (TCF3 gene) was more expressed in NR than in the VR and R xenografst, with a gradual increase among the 3 different groups starting from VR to NR xenografts. In addition, the upregulation of 3 genes (DSP, MITF, and WNT5B) was induced after CDDP treatment. Preliminary analysis on the same group of xenografts showed that CDDP treatment causes a modulation of CSC genes.

These new xenograft models will be instrumental in clarifying the role, if any, of EMT and CSCs in both predicting response to CDDP and in testing novel therapeutic strategies in ovarian carcinomas.

Citation Format: Francesca Ricci, Federica Guffanti, Maddalena Fratelli, Broggini Massimo, Giovanna Damia. Investigations on the role of epithelial-mesenchymal transition and cancer stem cells in the response to therapy in patient-derived ovarian carcinoma xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2015-4091