title: Role of deltaNp63(pos)CD44v(pos) cells in the development of N-nitroso-tris-chloroethylurea-induced peripheral-type mouse lung squamous cell carcinomas.
abstract: 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)CD44v(pos) 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 deltaNp63(pos)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.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Gi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tago
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukiyoshi
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tachibana
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology*; D002330:Carmustine / Q000031:analogs & derivatives / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000276:immunology; D011230:Precancerous Conditions / Q000473:pathology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D002273:Carcinogens; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C572573:N-nitroso-tris-chloroethylurea; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D002330:Carmustine
keywords: CD44(v9); N-nitroso-tris-chloroethylurea; deltaNp63; mice; squamous cell carcinoma