The role of cancer stem cells and the side population in epithelial ovarian cancer

Ovarian cancer is the most lethal cancer of the female reproductive tract, accounting for similar to 15,000 deaths per year according to the National Cancer Institute and American Cancer Society. This review article covers risk factors for the development of ovarian cancer, current detection strategies, prognostic markers, treatment strategies, etiology of tumorigenesis, and ovarian somatic stem cells. While the etiology of ovarian cancer is still unknown, several theories have been proposed as the mechanism of carcinogenesis. One theory states that the surface epithelium undergoing invagination and forming inclusion cysts that are exposed to growth factors and cytokines. The "gonadotropin theory" has also been proposed. Other reigning models for tumorigenesis include the stochastical model where a distinct population of cells acquires somatic mutations leading to metastasis, and the hierarchical model where the tumor is initiated by cancer stem cells (CSCs). CSCs isolated from primary tumors have the ability to regenerate the tumor and reconstitute the original tumor phenotype with as few as 100 cells. CSCs from ovarian carcinomas display the cell surface markers CD44(+)CD117(+)CD133(+). CSCs are also thought to account for chemotherapy resistance through the expression of highly selective transporters ABCG2 and MDR1 and activation of TLR4/MyD88. The side population has been characterized by their ability to efflux lipophilic substrates, including the dye Hoechst 33342 and many chemotherapy agents. This ability has been attributed to the expression of the transporters ABCG2 and MDR1.