Abstract
Papillomaviruses (PVs) induce papillomas, premalignant lesions, and carcinomas in a wide variety of species. PVs are classified first based on their host and tissue tropism and then their genomic diversities. A laboratory mouse papillomavirus, MmuPV1 (formerly MusPV), was horizontally transmitted within an inbred colony of NMRI-Foxn1nu/Foxn1nu (nude; T cell deficient) mice of an unknown period of time. A ground-up, filtered papilloma inoculum was not capable of infecting C57BL/6J wild-type mice; however, immunocompetent, alopecic, S/RV/Cri-ba/ba (bare) mice developed small papillomas at injection sites that regressed. NMRI-Foxn1nu and B6.Cg-Foxn1nu, but not NU/J-Foxn1nu, mice were susceptible to MmuPV1 infection. B6 congenic strains, but not other congenic strains carrying the same allelic mutations, lacking B- and T-cells, but not B-cells alone, were susceptible to infection, indicating that mouse strain and T-cell deficiency are critical to tumor formation. Lesions initially observed were exophytic papillomas around the muzzle, exophytic papillomas on the tail, and condylomas of the vaginal lining which could be induced by separate scarification or simultaneous scarification of MmuPV1 at all four sites. On the dorsal skin, locally invasive, poorly differentiated tumors developed with features similar to human trichoblastomas. Transcriptome analysis revealed significant differences between the normal skin in these anatomic sites and in papillomas versus trichoblastomas. The primarily dysregulated genes involved molecular pathways associated with cancer, cellular development, cellular growth and proliferation, cell morphology, and connective tissue development and function. Although trichoepitheliomas are benign, aggressive tumors, few of the genes commonly associated with basal cell carcinoma or squamous cells carcinoma were highly dysregulated.
Highlights
Papillomaviruses (PVs) are small DNA viruses that induce exophytic, sessile, and endophytic papillomas as well as squamous cell carcinomas in most mammalian species including humans [1]
To investigate the infectivity of MmuPV1 and its capability of inducing benign or malignant proliferative skin diseases at different anatomical sites, experimental infections were carried out using selected inbred mouse strains and congenic strains carrying a variety of single gene mutations that cause various forms of immunodeficiency (Table 1)
Since our initial and subsequent reporting of MmuPV1 experimentally infecting mice [24,25,26], there have been a number of other reports on MmuPV1
Summary
Papillomaviruses (PVs) are small DNA viruses that induce exophytic, sessile, and endophytic papillomas (lay term: warts) as well as squamous cell carcinomas in most mammalian species including humans [1]. New PV types are classified based on their degree of genetic relatedness to other known PVs, historically PVs were categorized as mucosotropic or cutaneotropic based on their tissue tropism. These characteristics hindered early development of a useful mouse model for human papillomavirus (HPV) infections. The cutaneotropic HPVs, such as EV (epidermodysplasia verruciformis) type HPVs (HPV5 and 8), can cause cancers in genetically immunocompromized individuals [5] or serve as a cofactor inducing other skin cancers [6, 7]. UV light may play a role in HPV-induced cancer [8, 9]
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