Development of a Novel Mouse Model of Spontaneous High-Risk HPVE6/E7–Expressing Carcinoma in the Cervicovaginal Tract
Open Access
- 2 July 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (17), 4560-4569
- https://doi.org/10.1158/0008-5472.can-21-0399
Abstract
Current preclinical models for cervical cancer lack important clinical and pathologic features. To improve upon these models, we aimed to develop a novel, spontaneous HPV16-expressing carcinoma model that captures major aspects of HPV-associated cancer in the female genital tract. This novel preclinical model features (i) expression of HPV oncogenes E6 and E7 in the tumors in female reproductive tract of mice, (ii) spontaneous progression through high-grade squamous intraepithelial lesion (HSIL) to carcinoma, and (iii) flexibility to model cancers from different high-risk HPV genotypes. This was accomplished by injecting plasmids expressing HPV16 E6/E7-luciferase, AKT, c-myc, and Sleeping Beauty transposase into the cervicovaginal tract of C57BL/6 mice followed by electroporation. Cell lines derived from these tumors expressed HPV16 E6/E7 oncogenes, formed tumors in immunocompetent mice, and displayed carcinoma morphology. In all, this novel HPV-associated cervicogenital carcinoma model and HPV16E6/E7–expressing tumor cell line improves upon current HPV16-E6/E7–expressing tumor models. These tumor models may serve as important preclinical models for the development of therapeutic HPV vaccines or novel therapeutic interventions against HPV E6/E7–expressing tumors. This study describes the development of a clinically relevant mouse model of cervicovaginal carcinoma that progresses from high-grade lesions and recapitulates key features of human HPV+ cervical cancer.Keywords
Other Versions
Funding Information
- National Institute of Health
- National Cancer Institute (R01CA237067, P50CA098252)
This publication has 36 references indexed in Scilit:
- Treatment Options for High-Grade Squamous Intraepithelial LesionsObstetrics and Gynecology Clinics of North America, 2013
- Oxidative Stress and HPV CarcinogenesisViruses, 2013
- Therapy of Human Papillomavirus-Related DiseaseVaccine, 2012
- A novel RT‐PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosisInternational Journal of Cancer, 2012
- De novo Induction of Genetically Engineered Brain Tumors in Mice Using Plasmid DNACancer Research, 2009
- Precancerous changes in the cervix and risk of subsequent preterm birthBJOG: An International Journal of Obstetrics and Gynaecology, 2007
- The E6AP Ubiquitin Ligase Is Required for Transactivation of the hTERT Promoter by the Human Papillomavirus E6 OncoproteinOnline Journal of Public Health Informatics, 2005
- Telomerase Activation by Human Papillomavirus Type 16 E6 Protein: Induction of Human Telomerase Reverse Transcriptase Expression through Myc and GC-Rich Sp1 Binding SitesJournal of Virology, 2001
- Myc activates telomeraseGenes & Development, 1998
- Vaccination with cytotoxic T lymphocyte epitope‐containing peptide protects against a tumor induced by human papillomavirus type 16‐transformed cellsEuropean Journal of Immunology, 1993