Abstract
Human papillomavirus (HPV) is the most common sexually transmitted pathogen, and high-risk HPVs contribute to 5% of human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). Despite the significant role played by HPVs in HNSCC, there is currently no available in vivo system to model the process from papillomavirus infection to virus-induced HNSCC. In this paper, we describe an infection-based HNSCC model, utilizing a mouse papillomavirus (MmuPV1), which naturally infects laboratory mice. Infections of the tongue epithelium of two immunodeficient strains with MmuPV1 caused high-grade squamous dysplasia with early signs of invasive carcinoma over the course of 4 months. When combined with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO), MmuPV1 caused invasive squamous cell carcinoma (SCC) on the tongue of both immunodeficient and immunocompetent mice. These tumors expressed markers of papillomavirus infection and HPV-associated carcinogenesis. This novel preclinical model provides a valuable new means to study how natural papillomavirus infections contribute to HNSCC.IMPORTANCE The species specificity of papillomavirus has limited the development of an infection-based animal model to study HPV-associated head and neck carcinogenesis. Our study presents a novel in vivo model using the mouse papillomavirus MmuPV1 to study papillomavirus-associated head and neck cancer. In our model, MmuPV1 infects and causes lesions in both immunodeficient and genetically immunocompetent strains of mice. These virally induced lesions carry features associated with both HPV infections and HPV-associated carcinogenesis. Combined with previously identified cancer cofactors, MmuPV1 causes invasive squamous cell carcinomas in mice. This model provides opportunities for basic and translational studies of papillomavirus infection-based head and neck disease.
Highlights
Levels of phospho-extracellular signal-regulated kinase (pERK) were elevated in our MmuPV1-induced tongue tumors, compared to those in mock-infected tongues (Fig. 4E). These results demonstrate that the tongue lesions caused by MmuPV1 infection resemble those associated with Human papillomavirus (HPV) infections, further validating the relevance of the use of MmuPV1 as an infection model for studying HPV-associated head and neck squamous cell carcinomas (HNSCCs)
In this study, we developed an in vivo infection model for studying papillomavirusinduced HNSCCs using MmuPV1
We showed that using our infection method, MmuPV1 could infect and cause high-grade dysplasia in immunodeficient mouse strains by 16 weeks
Summary
Human papillomavirus (HPV) is the most common sexually transmitted pathogen, and high-risk HPVs contribute to 5% of human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). When combined with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO), MmuPV1 caused invasive squamous cell carcinoma (SCC) on the tongue of both immunodeficient and immunocompetent mice These tumors expressed markers of papillomavirus infection and HPV-associated carcinogenesis. Combined with previously identified cancer cofactors, MmuPV1 causes invasive squamous cell carcinomas in mice This model provides opportunities for basic and translational studies of papillomavirus infection-based head and neck disease. We have previously shown that immunocompetent mice experimentally infected with MmuPV1 in their female reproductive tract developed cervical and vaginal cancers [28], much like high-risk HPVs in humans This observation led us to investigate whether MmuPV1 infections of mucosal epithelia in the head and neck region can progress to carcinoma
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