High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy
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Takuma Kagami1, Mihoko Yamade1, Takahiro Suzuki1, Takahiro Uotani1, Shinya Tani2, Yasushi Hamaya1, Moriya Iwaizumi3, Satoshi Osawa2, Ken Sugimoto1, Satoshi Baba4, Haruhiko Sugimura5, Hiroaki Miyajima1 and Takahisa Furuta6
1First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
2Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
3Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
4Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
5Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
6Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
Takuma Kagami, email: [email protected]
Keywords: cancer stem-like cell; CD44v8-10; esophageal cancer; chemoradiotherapy; sulfasalazine
Received: July 09, 2018 Accepted: September 13, 2018 Published: October 09, 2018
Background: Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance. In this study, we investigated the influence of CD44v8-10 expression on the overall survival of esophageal squamous cell carcinoma (E-SCC) patients after definitive chemoradiotherapy (dCRT) and on radio-sensitivities of E-SCC cell lines treated with or without sulfasalazine, a CD44v8-10-xCT-GSH axis inhibitor.
Methods: Seventy-three patients with E-SCC who received dCRT were examined retrospectively. CD44v8-10 expression was analyzed immunohistochemically using paraffin-blocked pre-dCRT biopsy specimens obtained by esophagoscopy and was expressed as a histo-score (H-score). The relationship between the H-score and overall survival was analyzed. From human E-SCC cell lines (T.T, T.Tn, or Kyse-3650), we collected CD44v8-10High and CD44v8-10Low subpopulations using a cell sorter. Water-soluble tetrazolium salt-8 (WST), glutathione-SH (GSH) and ROS assays were performed to compare the effect of sulfasalazine on the radio-sensitivities of these subpopulations in T.Tn and Kyse-3650.
Results: High CD44v8-10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277–6.611, p = 0.011). In CD44v8-10High cells of each cell line, sulfasalazine decreased cellular GSH levels, resulting in increased radiation-induced ROS and reduced cell viability. In contrast, sulfasalazine had no significant effects in CD44v8-10Low cells.
Conclusion: High CD44v8-10 expression was an independent prognostic factor in E-SCC patients treated with dCRT. CD44v8-10-xCT-GSH axis inhibition sensitized CD44v8-10High E-SCC cells to ROS-inducing treatments such as radiotherapy. Targeting CD44v8-10-xCT-GSH axis may improve the prognosis of post-dCRT E-SCC patients.
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