Co-targeting c-Met and COX-2 Leads to Enhanced Inhibition of Lung Tumorigenesis in a Murine Model with Heightened Airway HGF Laura P. Stabile, PhD, Mary.

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Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

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Co-targeting c-Met and COX-2 Leads to Enhanced Inhibition of Lung Tumorigenesis in a Murine Model with Heightened Airway HGF Laura P. Stabile, PhD, Mary E. Rothstein, BS, Christopher T. Gubish, MS, Diana E. Cunningham, MS, Nathan Lee, Jill M. Siegfried, PhD Journal of Thoracic Oncology Volume 9, Issue 9, Pages 1285-1293 (September 2014) DOI: 10.1097/JTO.0000000000000245 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Proliferation and invasion with single and combination treatments of celecoxib and crizotinib. A, 201T and 273T lung cancer cells were treated with celecoxib or crizotinib alone or in combination using the concentrations that inhibit 50% (IC50) of each drug for 72 hours. Relative cell proliferation was determined with each treatment. Control was set to 100. The results show significant differences between the combination treatment and each single agent and the control. Maximum decreases were observed with combination treatment. Similar results were obtained with the IC50 and IC25 conditions. ***p < 0.001, analysis of variance (ANOVA). B, 201T and 273T lung cancer cells were plated on Matrigel invasion chambers and were treated with celecoxib or crizotinib alone or in combination using the IC50 concentrations of each drug for 24 hours. Cells were fixed, stained, and counted for the number of invading cells. The combination treatment maximally inhibited cellular invasion in both cell lines. *p < 0.05; **p < 0.005; ***p < 0.001, ANOVA. n.s., Nonsignificant. Journal of Thoracic Oncology 2014 9, 1285-1293DOI: (10.1097/JTO.0000000000000245) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Representative cyclooxygenase-2 (COX-2) staining in lungs of hepatocyte growth factor transgenic (HGF TG) mice with and without NNK treatment. A, Control aged-matched lungs from HGF TG animals and (C) wild-type animals with no NNK treatment. B, HGF TG and (D) wild-type mouse lungs after animals were treated with 6-mg NNK and preneoplastic lesions were allowed to form for 10 weeks. These lesions are analogous to human atypical adenomatous hyperplasia. Lungs were formalin inflated and stained for COX-2 by immunohistochemistry. Representative images are shown. Red arrows represent COX-2-positive infiltrating leukocytes. Black arrows represent area of high-powered magnification. Journal of Thoracic Oncology 2014 9, 1285-1293DOI: (10.1097/JTO.0000000000000245) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, Boxplot of the number of tumors per mouse by treatment group analyzed by Poisson regression analysis. B, Boxplot of the log (tumor size mm2) by treatment group. A mixed effects model was used for analysis of tumor size. Horizontal line in box of boxplots represents the median. +, the mean; ; ns, nonsignificant. **p < 0.001; *p < 0.01. Journal of Thoracic Oncology 2014 9, 1285-1293DOI: (10.1097/JTO.0000000000000245) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Biomarkers modulated by treatment. P-c-Met, prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and P-MAPK expression was examined by immunohistochemistry in tumors arising from different treatment groups. Lungs were fixed in 10% buffered formalin. Lung samples were paraffin embedded, sliced, and mounted on slides. Representative staining for each marker and treatment group is shown. Quantitation was performed from three to five tumors per treatment group on a 1 to 4 scaling system, and determining the mean score. 1 = 1–25% positivity, 2 = 26–50% positivity, 3 = 51–75% positivity, and 4 76–100% positivity. Scale bar= 100 μm. Journal of Thoracic Oncology 2014 9, 1285-1293DOI: (10.1097/JTO.0000000000000245) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 EMT was modulated by single and dual treatment. Expression of E-cadherin and Snail was examined using immunohistochemistry in tumors arising from different treatment groups. Representative staining for each marker and treatment group is shown. Quantitation was performed from three to five high-powered tumor fields per area by counting the number of positive cells per field. ***p < 0.001; *p < 0.05. Scale bar = 50 μm. Journal of Thoracic Oncology 2014 9, 1285-1293DOI: (10.1097/JTO.0000000000000245) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions