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

摘要

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 deltaNp63^pos CD44v^pos CK5/6^pos CC10^pos clara cells as key constituents of early precancerous atypical bronchiolar hyperplasia. In addition, deltaNp63^pos CD44v^pos 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 deltaNp63^pos CD44v^pos 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 deltaNp63^pos style="fixed-case">CD44v^pos clara cells in mouse lung bronchioles might be the origin of the style="fixed-case">NTCU‐induced style="fixed-case">pLSCCs. Our findings also suggest that tumor‐associated macrophages may contribute to creating a tumor microenvironment in the peripheral area of style="fixed-case">pLSCCs that allows deltaNp63^pos style="fixed-case">CD44v^pos 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.