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Carcinogenesis ; 41(11): 1605-1615, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32221533

RESUMO

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis.


Assuntos
Carcinógenos/toxicidade , Endoscopia/métodos , Estrogênios/toxicidade , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias Vaginais/patologia , Animais , Carcinogênese , Feminino , Papillomavirus Humano 16/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase/fisiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias Vaginais/diagnóstico por imagem , Neoplasias Vaginais/etiologia , Neoplasias Vaginais/metabolismo
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