Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity to Chemoradiotherapy in Non-Small Cell Lung Cancer

Background. The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype; it has a profound impact on cancer progression. The purpose of this study was to clarify the role of EMT in the sensitivity of non-small cell lung cancer (NSCLC) to chemoradiotherapy (CRT). Methods. We evaluated the correlation between EMT and sensitivity to chemotherapy or radiotherapy using NSCLC cells induced to undergo EMT with epidermal growth factor or transforming growth factor-beta 1. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, cytokeratin, N-cadherin, and vimentin in 50 tumor specimens obtained from patients with NSCLC both before and after CRT. Results. The EMT resulted in increased malignant potential and reduced sensitivity to cisplatin and paclitaxel in NSCLC cells. Furthermore, chronic exposure to cisplatin, paclitaxel, or radiation altered the cells into therapy-resistant sub-lines that showed phenotypic changes such as a spindle-cell shape and increased EMT marker expression. Also, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after CRT compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors. Conclusions. The EMT marker expression was detected in NSCLC tumors after CRT, indicating that EMT changes are associated with insensitivity to CRT. New therapeutic combinations using EMT-signaling inhibitors may be needed to circumvent the resistance of some types of cancer to CRT. (Ann Thorac Surg 2011; 92: 1794-1804) (C) 2011 by The Society of Thoracic Surgeons