Epithelial Ovarian Cancer Stem Cells: 1 Underlying complexity of a simple paradigm. 2 3 4

Abstract 14 The lack of significant progress in treating epithelial ovarian cancer (EOC) underscores the need to gain a 15 better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem 16 cell hypothesis offers an attractive explanation of how subpopulations of cells within a patient’s tumour 17 might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant 18 disease. This review will examine the literature defining somatic stem cells of the ovary and fallopian 19 tube, two tissues which give rise to EOC. In addition, considerable research will be reviewed that has 20 identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, 21 EPCAM, LY6A, ALDH1 and side population), which are enriched for tumour initiating cells (TIC). While 22 many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little 23 consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the 24 identification of universal markers defining a cancer stem cell. The assay which forms the basis of 25 quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is 26 essential that some of the potential limitations be examined in this review. Highlighting such limitations 27 or weaknesses is required to properly evaluate data and broaden our interpretation of potential 28 mechanisms that might be contributing to the pathogenesis of ovarian cancer. 2