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HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice
Author(s) -
Mestre Verónica F,
MedeirosFonseca Beatriz,
Estêvão Diogo,
Casaca Fátima,
Silva Sandra,
Félix Ana,
Silva Fernanda,
Colaço Bruno,
Seixas Fernanda,
Bastos Margarida MSM,
Lopes Carlos,
Medeiros Rui,
Oliveira Paula A,
Gil da Costa Rui M
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5387
Subject(s) - pathology , tongue , biology , intraepithelial neoplasia , carcinogenesis , malignant transformation , lingual papilla , dysplasia , head and neck squamous cell carcinoma , immunohistochemistry , major duodenal papilla , cytokeratin , cancer research , cancer , head and neck cancer , medicine , anatomy , genetics , prostate
Head and neck squamous cell carcinomas (HNSCCs) associated with human papillomavirus (HPV) occur specifically in the tonsils and the tongue base, but the reasons for this specificity remain unknown. We studied the distribution of oral and pharyngeal lesions in HPV16‐transgenic mice where the expression of all the HPV16 early genes is targeted to keratinising squamous epithelia by the cytokeratin 14 ( Krt14 ) gene promoter. At 30 weeks of age, 100% of mice developed low‐ and high‐grade intraepithelial dysplasia at multiple sites. Twenty per cent of animals developed invasive cancers that remarkably were restricted to the tongue base, in association with the circumvallate papilla. The lesions maintained expression of CK14 (KRT14) and the HPV16 E6 and E7 oncogenes, and displayed deregulated cell proliferation and up‐regulation of p16 INK4A . Malignant lesions were poorly differentiated and destroyed the tongue musculature. We hypothesised that the tongue base area might contain a transformation zone similar to those observed in the cervix and anus, explaining why HPV‐positive cancers target that area specifically. Immunohistochemistry for two transformation zone markers, CK7 (KRT7) and p63 (TP63), revealed a squamocolumnar junction in the terminal duct of von Ebner's gland, composed of CK7 + luminal cells and p63 + basal cells. Dysplastic and invasive lesions retained diffuse p63 expression but only scattered positivity for CK7. Site‐specific HPV‐induced carcinogenesis in the tongue base may be explained by the presence of a transformation zone in the circumvallate papilla. This mouse model reproduces key morphological and molecular features of HPV‐positive HNSCC, providing a unique in vivo tool for basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.