Abstract 3411: Analysis of gene profile and identification of molecular targets in endometrial cancer stem cells

Abstract

Abstract Background; Cancer stem cells (CSCs) have been known to be the major source of tumor propagation and might be an attractive therapeutic target. Our previous study showed that CD133+ Ishikawa and MFE 280 endometrial cancer cells have the ability of tumorigenicity, self-renewal and differentiation capacity in vitro and in vivo, while CD133- cells did not. Furthermore, CD133+ cells showed more resistance to cisplatin- or paclitaxel-induced cytotoxicity than CD133- cells. These results indicate that CD133 is the CSC maker in endometrial cancer cells. In the present study, we sought to analyze gene profile and identify molecular targets in endometrial cancer stem cells. Methods; We examined microarray analysis to investigate the molecules essential for the CSCs characteristics by 3D-Gene chip (TORAY). Results; Microarray analysis of total 25,000 genes showed that about 500 genes were highly expressed in CD133+ cells, compared to CD133- cells. The ALDH1 gene was up-regulated in CD133+ cells, in accordance with the previous reported expression of ALDH1 on breast and colorectal CSCs. We also found out the elevated expression of ABC transporter genes, ABCG2, ABCG3, ABCG4, ABCG8, ABCC8 and ABCC9. It is well known that cells expressing those genes are resistant to chemotherapeutic agents and associated with side population (SP). Fluorescence activated cell sorter analysis demonstrated that the ratio of SP fraction in CD133+ Ishikawa cells is slightly higher than in CD133- Ishikawa cells (0.8% vs 0.6%). Isolated SP/CD133+ cells ells showed more extensive proliferation and tumorigenicity, compared with non-SP/CD133+, SP/CD133- and non-SP/CD133- cells. Finally, we focused on high expression of MMP14 (MT1-MMP) gene in CD133+ cells. Invasion assay revealed that CD133+ Ishikawa and MFE 280 cells have more invasive property than CD133- Ishikawa and MFE 280 cells. The inhibition of MT1-MMP gene by siRNA significantly reduced the invasive ability of CD133+ cells. These results suggest that MT1-MMP is one of the critical molecules that generate biological features of CSC and may be a potential therapeutic target in endometrial cancer. Conclusions; We demonstrated that SP/CD133+ cells might be more defined CSCs in endometrial cancer and identified important molecules essential for characterizing endometrial CSCs in which MT1-MMP plays critical roles in generating biological features of CSCs in this tumor type. These findings shed light on establishment of molecular target therapy in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3411. doi:10.1158/1538-7445.AM2011-3411