Unraveling the regulation of a putative cancer stem cell-like population in esophageal cancer.

Abstract

77 Background: Despite advances in the treatment of esophageal cancer (EC), most patients face poor outcome. Mounting evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. Whereas most cancer cells are sensitive to chemo- and/or radiotherapy (CRT), CSCs are generally resistant and ultimately have the potential to generate a new tumor. Mechanisms regulating EC CSCs are poorly understood and need to be elucidated. Previously, we identified a putative CSC-like population (CD24-/CD44+) in EC cell lines and in esophageal adenocarcinoma (EAC). Here we show that the Hedgehog signaling pathway may regulate CSC-like populations in EC. Methods: To identify up-regulated CSC related genes, qPCR arrays were performed on CD24-/CD44+ OE21 esophageal squamous cell carcinoma (ESCC) and OE33 (EAC). CD24-/CD44+ was compared to CD24+/CD44+ and solid tumors generated from the same cell lines obtained from xenografts. Immunohistochemical (IHC) staining from tumor material of microscopical residual disease (mRD) patients after CRT was compared to surgery alone patients (S). Results: From a panel of 84 CSC related genes, Ptch1 was found to be up-regulated in the OE21 CD24-/CD44+ putative CSC-like population when compared to CD24+/CD44+ population and the solid tumor (2.5 and 3.7 fold, respectively). Furthermore, in OE33 this up-regulation was 1.4 and 1.7 fold. From 6 preselected candidate CRT response markers, CD44 and Sonic Hedgehog (SHH) expression was 55% (p<0.05) and 64% (P<0.005) enhanced in mRD compared to the S group in IHC material. Moreover, SHH expression showed a positive correlation coefficient of 0.551 (P<0.005) with CD44 and 0.512 (P<0.05) with Excision Repair Cross-Complementation group 1 (ERCC1, a nucleotide excision repair gene) in mRD tissue. Conclusions: These findings indicate that the Hedgehog pathway might be involved in regulating EC CSC-like properties. Although requiring further research, an exciting prospect would be the modulation of the Hedgehog pathway in combating CSC-like populations and the potential predictive value of SHH expression on treatment outcome.