Comparative genomic analysis of side population in epithelial ovarian cancer

Abstract

[한글]

[영문]

Ovarian cancer is the fifth leading cause of cancer deaths and has the highest mortality rate among gynecologic cancers. It is more devastating in that it shows high response rate to initial therapy but most advanced diseases recur and become drug-resistant. Recent observations indicate that there is a small population of cancer cells, named as cancer stem cells (CSCs), which can self-renew and drive tumor growth. CSCs are thought to participate in the mechanisms of recurrence and drug resistance of ovarian cancer. Side population (SP) analysis is a valid marker-independent method to identify putative CSCs. SP has been reported to be enriched in tumorigenic and stem-like cells. In this study, to investigate the characteristics of ovarian CSCs, SP cells were isolated from cell lines primarily cultured from human epithelial ovarian cancer tissue, and then array comparative genomic hybridization (aCGH) was performed to analyze the specific genetic alteration for SP cells. Cell lines from a human ovarian cancer specimen showed heterogeneous populations with variation of surface marker expression, proliferation rate, cell cycle distribution, and SP fraction. There was SP fraction in range of less than 0.5% to 1% in the finally survived 3 clones. aCGH analysis revealed that 2383 genes were specifically altered in SP cells. These genes were involved in the networks, which top functions are cell cycle and cellular and embryonic development. Finally selected 64 genes were core molecules related to canonical pathways, such as Notch signaling, Wnt/β-catenin signaling, PTEN signaling, G1/S and G2/M checkpoint regulation, PI3K/AKT signaling, and p53 signaling. In review of literatures, there were common genetic changes between present study and previous reports, such as gain of 19p13.1, which is thought to be related to recurrence of ovarian cancer. These results indicate that the origin of CSCs is to some extent related to chromosomal instability and specific alteration happens in the genes participating in cell cycle and embryonic development. Characterization of the ovarian CSC would provide advance in developing novel therapeutics in the management of ovarian cancer.