title: Tumorigenic activity of merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice.
abstract: Merkel cell polyomavirus (MCPyV) is frequently associated with Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated copies of the viral genome with persistent expression of the MCPyV large T (LT) and small T (ST) antigen. MCPyV isolated from MCC typically contains wild-type ST but truncated forms of LT that retain the N-terminus but delete the C-terminus and render LT incapable of supporting virus replication. To determine the oncogenic activity of MCC tumor-derived T antigens in vivo, a conditional, tissue-specific mouse model was developed. Keratin 14-mediated Cre recombinase expression induced expression of MCPyV T antigens in stratified squamous epithelial cells and Merkel cells of the skin epidermis. Mice expressing MCPyV T antigens developed hyperplasia, hyperkeratosis, and acanthosis of the skin with additional abnormalities in whisker pads, footpads, and eyes. Nearly half of the mice also developed cutaneous papillomas. Evidence for neoplastic progression within stratified epithelia included increased cellular proliferation, unscheduled DNA synthesis, increased E2F-responsive genes levels, disrupted differentiation, and presence of a DNA damage response. These results indicate that MCPyV T antigens are tumorigenic in vivo, consistent with their suspected etiologic role in human cancer.
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Spurgeon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. james_decaprio@dfci.harvard.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000502:physiology*; D016667:Bacterial Capsules / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000502:physiology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D008297:Male; D059965:Merkel cell polyomavirus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010212:Papilloma / Q000209:etiology; D010641:Phenotype; D012878:Skin Neoplasms / Q000209:etiology*
chemical_list: D000957:Antigens, Viral, Tumor; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C039514:capsular polysaccharide K14