Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity to Chemoradiotherapy in Non-Small Cell Lung Cancer Yasushi Shintani, MD, PhD, Akira.

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Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity to Chemoradiotherapy in Non-Small Cell Lung Cancer Yasushi Shintani, MD, PhD, Akira Okimura, DDS, PhD, Katsutoshi Sato, PhD, Tomoyuki Nakagiri, MD, PhD, Yoshihisa Kadota, MD, PhD, Masayohi Inoue, MD, PhD, Noriyoshi Sawabata, MD, PhD, Masato Minami, MD, PhD, Naoki Ikeda, MD, PhD, Kunimistu Kawahara, MD, PhD, Tomoshige Matsumoto, MD, PhD, Nariaki Matsuura, MD, PhD, Mitsunori Ohta, MD, PhD, Meinoshin Okumura, MD, PhD The Annals of Thoracic Surgery Volume 92, Issue 5, Pages 1794-1804 (November 2011) DOI: 10.1016/j.athoracsur.2011.07.032 Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 (A) The A549 cells were treated with PBS (as a control), TGF-β1 (2 ng/mL), and EGF (100 ng/mL) for 2 days. Phase contrast images were obtained using a 4.2× objective lens. Bar = 100 μm. (B) The A549 cells were stained for E-cadherin, N-cadherin, 4',6-diamidino-2-phenylindole, and phalloidine after treatment with PBS (as a control) or TGF-β1 (2 ng/mL). Photographs were obtained using a 40× objective lens. Bar = 50 μm. (C) A549 cells were treated with PBS (control), TGF-β1 (2 ng/mL), or EGF (100 ng/mL) for 1 day, RT-PCR performed to detect E-cadherin and N-cadherin. (D) Motility assays were performed and cells traversing the filter were counted. Columns represent mean values, and bars the standard deviation (p < 0.05; control versus TGF or EGF). (con = control; EGF = epidermal growth factor; PBS = phosphate buffered saline; RT-PCR = real-time polymerase chain reaction; TGF = transforming growth factor.) The Annals of Thoracic Surgery 2011 92, 1794-1804DOI: (10.1016/j.athoracsur.2011.07.032) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 (A) The A549 cells were treated with cisplatin or paclitaxel after inducing EMT using TGF-β (2 ng/mL) or EGF (100 ng/mL). Proliferation of cells was quantified with MTT and clonogenic assays as described in the Material and Methods section; Cis, cisplatin (30 μM); Pac, paclitaxel (5 μM). The EMT-induced cells showed a significant increase in cell viability in response to cisplatin or paclitaxel. (B) Stable treatment-resistant phenotypes were generated by chronic exposure of A549 cells to cisplatin, paclitaxel, and radiation as described in the protocol noted in Materials and Methods section. Phase contrast images were obtained using a 4.2× objective lens. Bar = 100 μm. (C) Proliferation of resistant sub-lines was quantified with a clonogenic assay. (Con = untreated; Cis-R = cisplatin resistant; Pac-R = paclitaxel resistant; Rad-R = radiation-resistant sub-lines). Stable treatment-resistant phenotypes showed improved clonogenic survival in each resistant sub-line. (D) Total RNA was extracted from each resistant sub-line (Con = untreated; Cis = cisplatin resistant; Pac = paclitaxel resistant; RT, = radiation resistant), and real-time polymerase chain reaction was performed for E-cadherin, N-cadherin, and GAPDH (glyceraldehyde-3-phosphate dehydrogenase; as an internal control). (EMT = epithelial to mesenchymal transition; TGF = transforming growth factor.) The Annals of Thoracic Surgery 2011 92, 1794-1804DOI: (10.1016/j.athoracsur.2011.07.032) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Immunohistochemical staining was used to analyze the protein expressions of E-cadherin and cytokeratin as epithelial markers and of N-cadherin and vimentin as mesenchymal markers in tumors before and after chemoradiotherapy (CRT) treatment. All sections were scored in a semiquantitative manner as described in the protocol noted in Materials and Methods and the staining grade was classified as 0 (score < 10), +1 (10≤, <30), +2 (30≤, <70), or +3 (70≤). (A) Panels a–h show representative findings from a patient who received induction CRT followed by surgery. a–d: hematoxylin & eosin staining; e, f: E-cadherin staining; g, h: N-cadherin staining; a, c, e, g: pre-CRT; b, d, f, h: post-CRT. (B) a, b: E-cadherin staining; c, d: cytokeratin staining, e, f: N-cadherin staining; g, h: vimentin staining; a, c, e, g: pre- CRT; b, d, f, h: post- CRT. Scale bar = 50 μm. The Annals of Thoracic Surgery 2011 92, 1794-1804DOI: (10.1016/j.athoracsur.2011.07.032) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 (A) Disease-free survival (DFS) rates according to tumor expression of mesenchymal markers before chemoradiotherapy (CRT). (B) The DFS rates according to tumor expression of mesenchymal markers after CRT. (C) The DFS rates according to EMT changes in response to CRT. The DFS rate of patients with epithelial to mesenchymal transition (EMT) changes such as decreased epithelial markers and increased mesenchymal markers as response to CRT was significantly lower than that of patients without EMT changes. The Annals of Thoracic Surgery 2011 92, 1794-1804DOI: (10.1016/j.athoracsur.2011.07.032) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions