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

Takuma Kagami; Mihoko Yamade; Takahiro Suzuki; Takahiro Uotani; Shinya Tani; Yasushi Hamaya; Moriya Iwaizumi; Satoshi Osawa; Ken Sugimoto; Satoshi Baba; Haruhiko Sugimura; Hiroaki Miyajima; Takahisa Furuta

doi:10.18632/oncotarget.26172

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

Oncotarget. 2018 Oct 9;9(79):34876-34888. doi: 10.18632/oncotarget.26172.

Authors

Affiliations

¹ First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
² Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
³ Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁴ Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁵ Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁶ Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Abstract

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 CD44v8-10^High and CD44v8-10^Low 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 CD44v8-10^High 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 CD44v8-10^Low 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 CD44v8-10^High 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.

Keywords: CD44v8-10; cancer stem-like cell; chemoradiotherapy; esophageal cancer; sulfasalazine.