Role of deltaNp63posCD44vpos cells in the development of N‐nitroso‐tris‐chloroethylurea‐induced peripheral‐type mouse lung squamous cell carcinomas

• Published in: Cancer science Vol. 107; no. 2; pp. 123 - 132
• Main Authors: Yamano, Shotaro, Gi, Min, Tago, Yoshiyuki, Doi, Kenichiro, Okada, Satoshi, Hirayama, Yukiyoshi, Tachibana, Hirokazu, Ishii, Naomi, Fujioka, Masaki, Tatsumi, Kumiko, Wanibuchi, Hideki
• Format: Journal Article
• Language: English
• Published: 01.02.2016
• Subjects: CD44(v9); deltaNp63; mice; N‐nitroso‐tris‐chloroethylurea; squamous cell carcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12855

The role of cells expressing stem cell markers deltaNp63 and CD44v has not yet been elucidated in peripheral‐type lung squamous cell carcinoma (pLSCC) carcinogenesis. Female A/J mice were painted topically with N‐nitroso‐tris‐chloroethylurea (NTCU) for induction of pLSCC, and the histopathological and molecular characteristics of NTCU‐induced lung lesions were examined. Histopathologically, we found atypical bronchiolar hyperplasia, squamous metaplasia, squamous dysplasia, and pLSCCs in the treated mice. Furthermore, we identified deltaNp63posCD44vposCK5/6posCC10pos clara cells as key constituents of early precancerous atypical bronchiolar hyperplasia. In addition, deltaNp63posCD44vpos cells existed throughout the atypical bronchiolar hyperplasias, squamous metaplasias, squamous dysplasias, and pLSCCs. Overall, our findings suggest that NTCU induces pLSCC through an atypical bronchiolar hyperplasia–metaplasia–dysplasia–SCC sequence in mouse lung bronchioles. Notably, Ki67‐positive deltaNp63posCD44vpos cancer cells, cancer cells overexpressing phosphorylated epidermal growth factor receptor and signal transducer and activator of transcription 3, and tumor‐associated macrophages were all present in far greater numbers in the peripheral area of the pLSCCs compared with the central area. These findings suggest that deltaNp63posCD44vpos clara cells in mouse lung bronchioles might be the origin of the NTCU‐induced pLSCCs. Our findings also suggest that tumor‐associated macrophages may contribute to creating a tumor microenvironment in the peripheral area of pLSCCs that allows deltaNp63posCD44vpos cancer cell expansion through activation of epidermal growth factor receptor signaling, and that exerts an immunosuppressive effect through activation of signal transducer and activator of transcription 3 signaling. In summary, we demonstrate that NTCU‐induced lung cancers in mice are predominantly pLSCCs that are similar to human pLSCC. We also show that NTCU induced pLSCCs through an atypical bronchiolar hyperplasia‐metaplasia‐dysplasia‐SCC sequence. We identified deltaNp63posCD44vposCK5/6posCC10pos clara cells in atypical bronchiolar hyperplasias as a probable origin of pLSCCs in this model. Finally, a tumor microenvironment constructed with TAMs and deltaNp63posCD44vpos cancer cells in the peripheral area of pLSCCs is likely to be important for cancer progression in NTCU‐exposed mice.