Tumor and Stem Cell Biology SOX2 Expression Associates with Stem Cell State in Human Ovarian Carcinoma

The SRY-related HMG-box family of transcription factors member SOX2 regulates stemness and pluripotency in embryonic stem cells and plays important roles during early embryogenesis. More recently, SOX2 expression was documented in several tumor types including ovarian carcinoma, suggesting an involvement of SOX2 in regulation of cancer stemcells (CSC). Intriguingly, however, studies exploring the predictive value of SOX2 protein expression with respect to histopathologic and clinical parameters report contradictory results in individual tumors, indicating that SOX2may play tumor-specific roles. In this report, we analyze the functional relevance of SOX2 expression in human ovarian carcinoma. We report that in human serous ovarian carcinoma (SOC) cells, SOX2 expression increases the expression of CSC markers, the potential to form tumor spheres, and the in vivo tumor-initiating capacity, while leaving cellular proliferation unaltered. Moreover, SOX2-expressing cells display enhanced apoptosis resistance in response to conventional chemotherapies and TRAIL. Hence, our data show that SOX2 associates with stem cell state in ovarian carcinoma and induction of SOX2 imposes CSC properties on SOC cells. We propose the existence of SOX2-expressing ovarian CSCs as a mechanism of tumor aggressiveness and therapy resistance in human SOC. Cancer Res; 1–12. 2013 AACR. Introduction Pluripotency-associated stem cell factors such as OCT4 and SOX2 regulate cellular identity in embryonic stem cells and facilitate the reprogramming of terminally differentiated somatic cells back to a pluripotent stem cell state (1). SOX proteins are also important regulators of early development in different tissues, such as the foregut and lung, where for example SOX2 expression controls bronchogenesis by inhibiting airway branching (2, 3). In adult mice, SOX2 is expressed in different epithelial compartments marking cells with selfrenewal properties (4), and targeted ablation lethally disrupts epithelial tissue homeostasis (4). SOX2 expression is also found in neural stem cells, where it promotes stemness by preventing default differentiation into neurons (5). More recently, SOX2 expression has been shown in several tumor types such as lung (6–10), breast (11–14), skin (15, 16), prostate (17), ovarian (18, 19), sinonasal (20) as well as different types of squamous carcinomas (21). However, the SOX2 expression pattern and the correlation with histopathologic status and clinical outcome are highly variable among tumors, suggesting distinct roles of SOX2 in individual tumors. In breast carcinoma, SOX2 expression is mostly detected in a minor subset of tumor cells and seems to be an early event in tumor development (13), indicating potential roles in cancer stem cells (CSC) biology and involvement in reprogramming processes generating CSCs. In support of this notion, induction of SOX2 expression in breast carcinoma cell lines was shown to enhance CSC properties such as tumor sphere potential and in vivo tumorigenicity (12). Moreover, SOX2 expression was associated with positive lymph-nodal status in early-stage breast carcinoma (13). In contrast, in human squamous cell lung cancer, SOX2 protein overexpression was associated with smaller tumor size, lower probability of metastasis, and improved clinical outcome. Other than breast carcinoma, squamous cell lung cancer samples displayed homogenous SOX2 expression, arguing against specific roles of SOX2 in lung CSCs. Ovarian carcinoma has the seventh highest morbidity rate of cancer in women (22). Because of the lack of early specific symptoms, ovarian carcinoma is mostly diagnosed at advanced metastatic stages that cannot be cured by surgical Authors' Affiliations: Departments of Internal Medicine II and Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and ImagingTechnologyof theWernerSiemens-Foundation; Institute of Pathology; Interfaculty Institute for Biochemistry; Women's Hospital, University of Tuebingen, Tuebingen; Institute of Pathology, University of Bonn, Bonn; and German Cancer Consortium (DKTK) and German Cancer Research Center, Heidelberg, Germany Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). P.M. Bareiss andA. Paczulla contributed equally to thiswork and share first authorship. Corresponding Author: Claudia Lengerke, Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. Phone: 49-7071-29-82899; Fax: 49-7071-29-4524; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-12-4177 2013 American Association for Cancer Research. Cancer Research www.aacrjournals.org OF1 Research. on May 2, 2017. © 2013 American Association for Cancer cancerres.aacrjournals.org Downloaded from Published OnlineFirst July 18, 2013; DOI: 10.1158/0008-5472.CAN-12-4177