Cancer stem cells and chemoresistance in ovarian cancer

The high mortality rate associated with epithelial ovarian cancer (EOC) is due to its insidious onset, leading to late diagnosis as well as eventual development of chemoresistance in the majority of patients. Cancer stem-like cells (CSCs) are thought to contribute to development of multi-drug resistant (MDR) tumours partly through their high level of ABC-transporter expression, which enables them to survive chemotherapy.
ABC-transporter (MRP1, MRP2, BCRP, Pgp) and putative CSC-marker (ALDH1A1, CD44) expression was therefore evaluated by immunohistochemistry in a paraffin-embedded cohort of 57 high-grade EOC tumours. Typically 9-12% of cells in tumours expressed CD44 / ALDH1A1. These may represent a population enriched for CSCs. ABC-transporters were expressed in 10- 43% of cells on average. Using Spearman rank test, there was no correlation between CSC- marker and ABC-transporter expression, however correlation was observed between many of the ABC-transporters, suggesting existence of highly drug-resistant populations within tumours. Expression of CA125 (a glycoprotein expressed by EOC cells and used clinically to detect EOC relapse) and EpCAM (a cell adhesion molecule expressed by EOC cells) was also investigated. Interestingly, patient tumours with the highest level of EpCAM had longer overall survival by Kaplan-Meier analysis. In addition, increased expression of MRP1 and CD44 predicted poorer patient outcome by Cox regression analysis.
In vitro functional assays were also used to identify CSCs. Cells derived from ascites samples had a mean colony-forming efficiency (CFE) or 6.3%, and in unsorted tumours this was 11.4%. Cancer cells were then isolated from primary ascites and tumour samples (using CA125 and EpCAM). On average, self-renewing assays revealed a 2.2-2.4-fold increase in CFE for CA125 or EpCAM positive sorted cells compared to CA125 or EpCAM negative cells. Future studies could characterise these self-renewing populations, which may lead to identification of novel CSC targets for use in EOC treatment.