Abstract A36: Protein markers of tumor-initiating cells and mitochondrial function in ovarian cancer

Abstract

Abstract Background: Epithelial ovarian carcinoma (EOC) is the 5th leading cause of total cancer death in women. Despite initial responsiveness to treatment, >75% of patients relapse into metastatic and essentially incurable chemoresistant disease. In carcinomas, metastasis is associated with the dedifferentiation process termed epithelial-to-mesenchymal transition (EMT). EMT is molecularly related to a cancer stem cell phenotype. Cancer stem cells, or tumor-initiating cells (TICs) as they are now called, are increasingly believed to underlie relapse, and are by definition highly chemoresistant and able to give rise to metastases. By repeated cisplatin treatment of the EOC cell line SKOV-3, originating from malignant ascites, we have created a stable subline (SKOV-3-R) expressing TIC markers, and showing EMT, increased motility, sphere formation in stem cell medium. They also show increased mitochondrial content and expression of mitochondrial VDAC, and hexokinase-II (HK-II) known to be upregulated in glycolytic tumor cells [1]. The chemoresistance of SKOV-3-R was found to depend on HK-II [1]. The role of altered mitochondrial functions in tumor progression and in TICs is attracting increased attention. Aim: To examine and correlate expression of TIC markers and mitochondrial markers in clinical samples, and to relate these to EOC subtype and hormone receptor status. Results: SKOV-3-R expresses TIC markers CD117, CD44 and ALDH1. Cells freshly isolated from malignant EOC ascites were analysed for TIC markers CD117, CD44, EpCAM and Nanog, and loss of E-cadherin as a marker of EMT. In an immunohistochemical pilot study on 60 patient samples we now examine expression of CD117, CD44, ALDH1, and VDAC and HK-II. Discussion: The SKOV-3-R results indicate that these cells constitute an in vitro model of TICs and that they have increased mitochondrial content. The analysis of malignant ascites shows potentially high levels of TICs in ascites. Results of immunhistochemical analysis of tumors are pending (August, 2013). 1. Wintzell M, Lofstedt L, Johansson J, Pedersen AB, Fuxe J, Shoshan M: Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate. Cancer Biol Ther 2012, 13(14):1454-1462. Citation Format: Marike Gabrielson, My Björklund, Joseph Carlson, Maria Shoshan. Protein markers of tumor-initiating cells and mitochondrial function in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A36.