Abstract 1155: Stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer
Authors: Narusaka Toru , Ohara Toshiaki , Noma Kazuhiro , Katsura Yuki , Nishiwaki Noriyuki , Tabuchi Motoyasu , Fushimi Takuro , Ogawa Toshihiro , Takeda Sho , Komoto Satoshi , Sato Hiroaki , Kikuchi Satoru , Tomono Yasuko , Tazawa Hiroshi , Kagawa Shunsuke , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: August 2019

Abstract
Background:Esophageal cancer has a poor prognosis and high mortality rate because of recurrence and chemo-resistance. Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiation, drug resistance, and recurrence. Although CSCs are considered to be important therapeutic targets, effective CSC targeted therapy has not yet been established. We previously reported that iron chelator suppressed not only proliferation but also the expression of stemness markers in mouse induced pluripotent stem cells (miPS) and miPS inducible CSC model cells (miPS-LLCcm). Moreover, we revealed that iron chelator also suppressed the expression of stemness markers and function in esophageal cancer cell lines with high stemness potential. Thus we hypothesized that stemness control by iron chelator can be a novel therapeutic strategy for esophageal cancer patients. In this study, we performed clinicopathological analysis using primary tissue samples, verified the possibility of clinical study, and explored the mechanisms in vitro.Method: TE-8 and OE33 were used as esophageal cancer cell lines expressing stemness markers. Deferasirox (DFX) and Deferoxamine (DFO) were used as iron chelator. The stemness markers expression including Nanog, Sox2, Oct3/4, Klf-4 and c-Myc was examined by western blot analysis. Reactive oxygen species (ROS) generation was examined by fluorescence staining. Immunohistochemistry (IHC) of Nanog was performed in 134 clinical esophageal cancer patients who received radical esophagectomy in Okayama university hospital. Result: DFX and DFO suppressed the expression of stemness markers although cisplatin could not suppress. DFX and DFO induced ROS generation. Nanog IHC staining revealed that high Nanog expression was correlated with low overall survival (OS) (HR, 2.53 [95% CI, 1.24 to 5.14]; P = 0.01) and disease-free survival (DFS) (HR, 2.33 [95% CI, 1.19 to 4.58]; P = 0.01). Moreover, high Nanog expression was also correlated with low OS in neoadjuvant therapy group, but not in non-neoadjuvant therapy group.
Conclusion: Iron chelator, DFX and DFO, suppressed proliferation and stemness via ROS generation in esophageal cancer cell lines. High Nanog expression was correlated with poor prognosis, which indicates that stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer patients.
Citation Format: Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Noriyuki Nishiwaki, Motoyasu Tabuchi, Takuro Fushimi, Toshihiro Ogawa, Sho Takeda, Satoshi Komoto, Hiroaki Sato, Satoru Kikuchi, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1155.