N-nitroso-tris-chloroethylurea induces pre-malignant squamous dysplasia in mice

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2011-11, Vol.5 (2), p.283-289
• Main Authors: Hudish, Tyler M., Opincariu, Laura I., Mozer, Anthony B., Johnson, Micah S., Cleaver, Timothy G., Malkoski, Stephen P., Merrick, Daniel T., Keith, Robert L.
• Format: Article
• Language: English
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-11-0257

Squamous cell carcinoma (SCC) and pre-malignant endobronchial lesions have been difficult to study in murine models. In this report, we evaluate the topical N-nitroso-tris-chloroethylurea (NTCU) murine SCC model, determine the extent to which resulting pre-malignant airway dysplasia develops, discuss clinicopathologic grading criteria in lesion progression, and confirm that immunohistochemical (IHC) staining patterns are consistent with those observed in human endobronchial dysplasia and SCC. Male and female FVB mice were treated biweekly with topical NTCU (4, 8, or 40mM) or vehicle for 32 weeks. Following sacrifice, squamous cell lesions were enumerated and categorized into the following groups: flat atypia, low-grade dysplasia, high-grade dysplasia, and invasive SCC. The 40mM NTCU concentration produced the entire spectrum of premalignant dysplasias and squamous cell carcinomas, but was associated with poor survival. Concentrations of 4mM and 8mM NTCU were better tolerated and produced only significant levels of flat atypia. Squamous origin of the range of observed lesions was confirmed with IHC staining for cytokeratin 5/6, p63, thyroid transcription factor-1 (TTF-1), and Napsin-A. This study demonstrates that topical application of high dose NTCU produces endobronchial pre-malignant lesions with classic squamous characteristics and should allow for improved pre-clinical evaluation of potential chemopreventive agents.