Increased Incidence of Squamous Cell Carcinomas in Mastomys natalensis Papillomavirus E6 Transgenic Mice during Two-Stage Skin Carcinogenesis

Abstract

Papillomaviruses cause certain forms of human cancers, most notably carcinomas of the uterine cervix. In contrast to the well-established involvement of papillomavirus infection in the etiology of cervical carcinomas and in carcinomas of a rare hereditary condition, epidermodysplasia verruciformis, a causative role for cutaneous human papillomavirus types in the development of nonmelanoma skin cancer has not been proven. In order to better understand the functions of individual genes of cutaneous papillomavirus types, we generated transgenic mice carrying oncogene E6 of the Mastomys natalensis papillomavirus (MnPV), which causes keratoacanthomas of the skin in its natural host. In the present study, we demonstrate that under conditions of experimental two-stage skin carcinogenesis, fast-paced squamous cell carcinomas develop in nearly 100% of MnPV E6 transgenic mice in comparison to 10% in their nontransgenic littermates (log rank test; P < 0.0001). Therefore, we conclude that the MnPV E6 transgene favors the malignant progression of chemically induced tumors. Whereas an activating H-ras mutation is a consistent feature in benign and malignant tumors in wild-type mice, the majority of papillomas and keratoacanthomas and all squamous cell carcinomas obtained in MnPV E6 transgenic mice contain nonmutated ras alleles. These results indicate that the development of squamous cell carcinomas in MnPV E6 transgenic mice does not depend on an activated H-ras oncogene.Papillomaviruses are widely known to play a causative role in the development of tumors in humans. Certain genotypes cause mostly benign epidermal tumors in humans and animals. Another subgroup of genotypes, the so-called "high-risk" anogenital human papillomavirus (HPV) types, are causally involved in the development of malignant tumors, such as carcinoma of the cervix (17, 47, 49). The carcinogenic potential was first detected in 1935, when Rous and Bernard showed that inoculation into domestic rabbits of the filterable extracts from warts of cottontail rabbits was able to induce skin carcinomas (37). A direct involvement of cutaneous HPV types in the development of squamous cell carcinomas, one of the most frequent malignancies in humans of Caucasian origin, is suspected but still not proven (7, 34). The earliest hints of an involvement of specific HPV types in human skin cancer originated from studies of patients suffering from the very rare hereditary disease epidermodysplasia verruciformis (EV) (32,21). Only a limited number of HPV types, commonly referred to as EV-HPV types, such as HPV5, -8, and -14, are frequently detected in squamous cell carcinomas that develop in ϳ30% of cases within multiple flat warts in sun-exposed areas of the skin in such patients (25). More recent data suggested a role for EV-related papillomaviruses in the origin of skin cancer in immunosuppressed patients (39) and those with renal transplants (28). Thus, specific high-risk cutaneous HPV types comparable to carcinogenic anogenital HPV types have not been identified (48,49)...

Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

“…Transgenic IRCxFVB mice with keratin-1 promoter-driven E6/E7 genes of the cervical cancer associated HPV18 developed papillomas that remained benign for up to 12 months (36). The K14-promoter-driven oncogene E6 of the Mastomys natalensis PV, which causes keratoacanthomas in its natural host, did not perturb normal skin differentiation per se but favored malignant progression of chemically induced tumors (30). Only the high penetrance of papillomatosis and dysplasia in K14-HPV16 transgenic mice (37) is comparable with HPV8 transgenics.…”

“…The HPV8 transgenes are under control of the cytokeratin-14 promoter, which is well known to target expression to the epidermis and developing hair follicles of mouse embryos and to basal and spinous layers of the adult skin (29)(30)(31). The early HPV genes are transcribed as multiple polycistronic messages generated by alternative splicing (32,33).…”

HPV‐associated skin disease

“…Molecular studies on the skin tumours of these transgenic animals revealed strong gelatinolytic activity, which could be attributed to MMP‐9 and the up‐regulation and activation of MMP‐13 and MT1‐MMP 75. The high penetrance of papillomatosis followed by progression to dysplasia is remarkable and in contrast to many other HPV‐transgenic mice models 73, 76, 77. Only the high penetrance of papillomatosis and dysplasia in K14‐HPV 16 transgenic mice 78 is comparable with HPV 8 transgenics.…”

Skin Hyperproliferation and Susceptibility to Chemical Carcinogenesis in Transgenic Mice Expressing E6 and E7 of Human Papillomavirus Type 38

“…In contrast to mucosal HPV16 E6/E7-Tg or EV HPV8-Tg mice (18,29,31), HPV38 E6/E7 animals did not develop spontaneous tumors or any skin lesions during their life span of approximately 2 to 2.5 years. Therefore, we checked whether HPV38 E6 and E7 cooperate with chemical carcinogens to induce skin tumors in our Tg mouse model, as previously shown for other papillomaviruses (12,30). Non-Tg (FVB/N, 13 animals), HPV16 E6/E7-Tg (12 animals), and HPV38 E6/E7-Tg (8 for each line) mice were exposed to a two-stage carcinogen treatment with DMBA and TPA (Fig.…”