title: Tracheal dysplasia precedes bronchial dysplasia in mouse model of N-nitroso trischloroethylurea induced squamous cell lung cancer.
abstract: Squamous cell lung cancer (SCC) is the second leading cause of lung cancer death in the US and has a 5-year survival rate of only 16%. Histological changes in the bronchial epithelium termed dysplasia are precursors to invasive SCC. However, the cellular mechanisms that cause dysplasia are unknown. To fill this knowledge gap, we used topical application of N-nitroso-tris chloroethylurea (NTCU) for 32 weeks to induce squamous dysplasia and SCC in mice. At 32 weeks the predominant cell type in the dysplastic airways was Keratin (K) 5 and K14 expressing basal cells. Notably, basal cells are extremely rare in the normal mouse bronchial epithelium but are abundant in the trachea. We therefore evaluated time-dependent changes in tracheal and bronchial histopathology after NTCU exposure (4, 8, 12, 16, 25 and 32 weeks). We show that tracheal dysplasia occurs significantly earlier than that of the bronchial epithelium (12 weeks vs. 25 weeks). This was associated with increased numbers of K5+/K14+ tracheal basal cells and a complete loss of secretory (Club cell secretory protein expressing CCSP+) and ciliated cells. TUNEL staining of NTCU treated tissues confirmed that the loss of CCSP+ and ciliated cells was not due to apoptosis. However, mitotic index (measured by bromodeoxyuridine incorporation) showed that NTCU treatment increased proliferation of K5+ basal cells in the trachea, and altered bronchial mitotic population from CCSP+ to K5+ basal cells. Thus, we demonstrate that NTCU-induced lung epithelial dysplasia starts in the tracheal epithelium, and is followed by basal cell metaplasia of the bronchial epithelium. This analysis extends our knowledge of the NTCU-SCC model by defining the early changes in epithelial cell phenotypes in distinct airway locations, and this may assist in identifying new targets for future chemoprevention studies.
authors: Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
authors: Moumita
authors: M
authors: Ghosh
authors: Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States of America.
authors: Lori D
authors: LD
authors: Dwyer-Nield
authors: Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
authors: Jennifer B
authors: JB
authors: Kwon
authors: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors: Lea
authors: L
authors: Barthel
authors: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
authors: William J
authors: WJ
authors: Janssen
authors: Department of Pathology, University of Colorado, Aurora, Colorado, United States of America.
authors: Daniel T
authors: DT
authors: Merrick
authors: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Denver Veteran Affairs Medical Center, Denver, Colorado, United States of America.
authors: Robert L
authors: RL
authors: Keith
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001980:Bronchi / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000473:pathology*; D002330:Carmustine / Q000009:adverse effects / Q000031:analogs & derivatives*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D008940:Mitotic Index; D060787:Neoplasm Grading; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D014132:Trachea / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C572573:N-nitroso-tris-chloroethylurea; D002330:Carmustine