ALDH1+ cancer stem cells in epithelial ovarian cancer are associated with chemoresistance and poor survival

Introduction: Although epithelial ovarian cancer (EOC) is chemosensitive, the frequent occurrence of drug resistance in the course of the disease persists to be a problem and is a key factor in the high mortality rate. Cancer stem cells (CSCs) are defined as malignant cells with a stem cell phenotype. They have the exclusive ability to self-renew and maintain the tumor. CSCs have also been suggested to contribute to chemoresistance. Thus, identification and characterization of CSCs might fuel the development of CSC-targeted therapeutics and improve survival rates. Methods: The study population consisted of a retrospective sample of 66 patients with EOC (serous-papillary, FIGO IIIc/IV) diagnosed at Bonn University between 2002 and 2012 and treated with I-III cycles of taxane/platinum-based neoadjuvant chemotherapy and cytoreductive surgery. Expression analysis was performed immunohistochemically with ALDH1, CD117, CD24 and CD133 using matched pairs of tumor tissue before and after chemotherapy. Flow cytometry helped to separate CSCs from other stem cell marker-positive cells. Results: Since no universal indicator for CSCs is known, we used four established markers to characterize CSCs. Only ALDH1 was able to identify CSCs with clinical relevance. ALDH1 + cells accumulated with increasing cycles of chemotherapy. Further, a high number of ALDH1 + cells after chemotherapy correlated with short progression-free and overall survival. Discussion: ALDH1 indicates poor patient survival and defines CSCs that exhibit resistance to treatment with genotoxic agents. This may give us the opportunity to identify patients that would not benefit from further chemotherapy but might profit from novel CSCs-targeted strategies.