Abstract
BackgroundStrong 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.MethodsSeventy-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.ResultsHigh 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.ConclusionHigh 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.
Highlights
CD44 is a cell adhesion molecule of the extracellular matrix and has many functions in leucocyte homing/ activation, wound healing, cell migration, and tumor invasion/metastasis [1,2,3]
Univariate analysis showed that performance status (PS), tumor size, clinical stage (cStage) and high CD44v8-10 expression were associated with poor prognosis (Table 2)
The Cox proportional hazard model using CD44v8-10 expression (H-score) as a continuous variable further confirmed that CD44v8-10 was an independent poor prognostic factor for overall survival (HR = 1.009, 95% confidence interval (CI) 1.004–1.015, p = 0.002 for CD44v8-10 expression in univariate analysis; hazard ratio (HR) = 1.008, 95% CI 1.002–1.014, p = 0.009 for CD44v8-10 expression in multivariate analysis)
Summary
CD44 is a cell adhesion molecule of the extracellular matrix and has many functions in leucocyte homing/ activation, wound healing, cell migration, and tumor invasion/metastasis [1,2,3]. CD44 has many splice-variant isoforms, which contribute to heterogeneity in tumor cells. The CD44 isoform containing variant exon 9 (CD44v9) is a known marker for cancer stem-like cells in many types of cancers. Therapeutic resistance of cancer stem-like cells has been identified in various solid tumors. CD44v9 was first reported as a cell surface marker associated with recurrence and mortality for gastric cancer in 1993 [4]. CD44v8-10 expression in esophageal cancer and its clinical significance have not been fully elucidated. Strong reactive oxygen species (ROS) suppression in cancer stemlike cell components in various solid tumors is associated with therapeutic resistance. 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
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