Abstract 3471: Paclitaxel selects and enriches for CD44+/MyD88+ ovarian cancer stem cells

Abstract

Abstract Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The current standard of care in the treatment of EOC patients is surgical debulking and combination chemotherapy usually with Carboplatin and Paclitaxel. Although effective in majority of the cases, more than 20% of patients do not respond. Moreover, more than 80% of patients present with recurrent disease within 5 years. Therefore, there is an underlying biology that results in the differential response to treatment as well as the occurrence of recurrent disease. Tumors are heterogeneous and consist of multiple types of cancer cells, which exhibit different chemoresponsiveness. Our group previously described the characterization of CD44+/MyD88+ EOC stem cells and demonstrated their tumor-initiating properties. An important characteristic of these cells, which differentiate them from the CD44-/MyD88- EOC cells, is the presence of a functional TLR4-MyD88-NFkB pathway. This pathway confers Paclitaxel resistance to these cells. We hypothesize that a cause for recurrence following Paclitaxel treatment is the selective survival of cancer stem cells capable to recreate the tumor. In this study, we demonstrate that Paclitaxel enriches for the CD44+/MyD88+ EOC stem cells thus promoting recurrence. Methods: In vitro model: co-culture system consisting of (50%:50%) GFP+ CD44+/MyD88+ and RFP+ CD44-/MyD88- cells treated with 0.2 uM Paclitaxel. In vivo model: Ovarian tumors implanted s.c in Nude mice treated with 10 mg/kg Paclitaxel q3d for 21 days. Levels of GFP+ and CD44+ cells were determined by flow cytometry. Klf-4, Nanog, MyD88, and ALDH1 were determined by qPCR or western blot. Results: Control co-cultures were characterized by overgrowth of CD44-/MyD88- EOC cells while the Paclitaxel treated co-cultures had mainly CD44+/MyD88+ EOC stem cells. Similarly in vivo results show enrichment in CD44+ cells with Paclitaxel (49% CD44+ in control vs 88% CD44+ with treatment). Analysis of genes associated with stemness showed upregulation of Klf-4, Nanog ALDH1, and MyD88 in the cultures treated with Paclitaxel compared to control. Conclusion: We demonstrate that Paclitaxel selectively induce cell death in CD44-/MyD88- EOC cells but has a pro-survival effect and enhances self-renewal in the pleuripotent and chemoresistant CD44+/MyD88+ EOC stem cells. Based on these data, we propose that the mode of management for EOC patients should take into consideration the tumor's molecular phenotype. Our results highlight the need to identify patients that should not receive Paclitaxel - not only because they are resistant, but more importantly, because it can enrich for the more aggressive cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3471. doi:1538-7445.AM2012-3471