Abstract 3408: Ovarian cancer stem cell cytokine microenvironment

Abstract

Abstract Objectives: Epithelial ovarian cancer (EOC) is an extremely aggressive disease associated with a lack of early symptoms, rapid progression to peritoneal metastases, and poor prognosis for patients. Currently available treatments are not effective in preventing or slowing metastatic spread, and the therapeutic resistance of EOC remains a major unresolved clinical and scientific problem. Cancer stem cells (CSCs) represent the most aggressive part of the tumor. CSCs are drug resistant and are thought to be responsible for the failure of chemotherapy. Earlier, we demonstrated that chemotherapy can lead to selection of CSCs. We hypothesized that malignancy of CSCs was associated with an efficient cytokine network. Methods: Ovarian CSCs and primary adherent epithelial cultures were established from ascites from ovarian cancer patient with stage III EOC. Ovarian CSCs were isolated using magnetic beads separation columns and human CD133 and CD44 Microbead kits from Miltenyl Biotec and were grown as tumor spheres. The High Content Screening (HCS) and High Content Analysis (HCA) platform from Thermo Scientific Cellomics was applied to study the CSC markers, embryonic markers, transcription factors, epithelial mesenchimal transition markers, cytokines, chemokines, growth and angiogenetic factor receptor expression and intracellular cytokine accumulation. Multiplex xMAP technology was used for the analysis of human cytokines and growth factors in cell culture medium. An in vivo SCID mouse model was used for the analysis of tumorigenity of bulk EOC cells and CSCs. Results: We established primary EOC cell lines and CSCs from ascites of 3 EOC patients. We confirmed that cells growing in tumor spheres demonstrate all the properties of CSCs: they express high levels of CSCs markers and low levels of differentiated markers, they have capacity to self-renew and differentiate, and they are highly tumorigenic in SCID mice. The EMT and CSC phenotypes were both exhibited in ovarian CSCs. We found that ovarian CSCs have a specific cytokine microenvironment involving the up-regulation of multiple cytokine-receptor axes. Conclusions: Our findings provide new knowledge regarding ovarian CSC biology. They elucidate the important role of the specific cytokine-receptor signaling axis for the self-renewal and proliferation of ovarian CSCs. We concluded that an optimal antitumor efficacy will be achieved by inhibiting both tumor cell populations: CSCs and bulk EOC cells. We suggest that combining two treatment modalities, e.g. RTK inhibitor that targets CSCs, and cisplatin that eradicates bulk tumor cells will represent a novel paradigm in EOC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2011-3408