Mesenchymal phenotype after chemotherapy is associated with chemoresistance and poor clinical outcome in esophageal cancer

The relationship between the epithelial-mesenchymal transition (EMT) and resistance to anticancer treatment has attracted attention in recent years. However, to date, there is no direct clinical evidence for a link between the mesenchymal phenotype and chemoresistance in human malignancies. The expression of EMT-related markers, including E-cadherin, Snail, vimentin, ZEB1, β-catenin and N-cadherin was examined immunohistochemically in 185 tissue samples from patients with esophageal cancer (including 93 patients who received preoperative chemotherapy followed by surgery and 92 patients who underwent surgery without preoperative therapy). The relationship between the expression of the above markers and clinical outcome including prognosis and response to chemotherapy was also examined. The expression of E-cadherin, a marker of epithelial cells, was significantly lower in residual tumors than chemo-naive tumors (P=0.003). The expression of Snail (P=0.028), ZEB1 (P<0.001) and N-cadherin (P=0.001), markers of mesenchymal cells, was higher in residual tumors than in chemonaive tumors. The expression of E-cadherin correlated inversely with that of Snail (P<0.001). Reduced expression of E-cadherin and increased expression of Snail in residual tumors from patients who received chemotherapy correlated significantly with poor response to chemotherapy and short survival time. Multivariate analysis identified Snail expression as an independent prognostic factor, along with tumor depth, in patients who received preoperative chemotherapy for esophageal cancer. The results suggest transition of residual esophageal cancer cells to mesenchymal phenotype after chemotherapy and this contributes to resistance to chemotherapy and poor prognosis in patients with esophageal cancer.