Research in transgenic mice has demonstrated that expression of oncogenes E6 and E7 from a cutaneous beta human papillomavirus (HPV38), coupled with UVB exposure, results in high rates of nonmelanoma skin cancer. Neither factor by itself was sufficient to generate tumors in the animals.
National report - Research in transgenic mice has demonstrated that expression of oncogenes E6 and E7 from a cutaneous beta human papillomavirus (HPV38), coupled with UVB exposure, results in high rates of nonmelanoma skin cancer. Neither factor by itself was sufficient to generate tumors in the animals.
This raises the theoretical possibility of developing a vaccine to better stimulate an immune response that might hold the virus in check and prevent the development of skin cancers. The findings appeared in the open access journal PLoS Pathogens.
Human papillomavirus is part of a large family consisting of more than 200 distinct viral types, each adapted to a particular tissue environmental niche. Approximately 40 different beta HPV types have been identified in the skin and appear to be part of the normal skin flora. They are frequently detected in the skin of normal individuals, whose immune system keeps the infection under control.
The senior author of the paper is a researcher with the World Health Organization International Agency for Research on Cancer in Lyon, France.
Earlier work on different HPV types demonstrated that the product of two early genes, E6 and E7, play a key role in the induction of cellular proliferation and inhibition of apoptosis as well as senescence. This greatly increases the probability that HPV-infected cells will evolve toward malignancy. The E6 and E7 genes from HPV16, the etiological agent of cervical cancer, have the property to immortalize primary human keratinocytes in vitro.
Dr. Tommasino says the E6 and E7 proteins from HPV38 are similar to the ones from HPV16 and display several transforming properties, including the ability to immortalize primary cells.
"In natural infection, if the immune system works efficiently, it rapidly eliminates these infected cells and there will be no development of disease," he says. "But if the virus is able to persist for many years, then there is a high probability that the infected cells will acquire the transformed phenotype." The difference between benign and oncogenic HPV types probably comes down to the efficiency of their E6 and E7 proteins in carrying out those disruptive functions, he says.
This latest study carried the research forward into a transgenic mouse model in which the E6 and E7 genes were expressed in the undifferentiated basal layer of epithelia. Wild type animals exposed to UV irradiation showed normal cell morphology, but the transgenic animals exposed to those same challenges showed cellular tissue transformation similar to what is seen with actinic keratosis and squamous cell carcinoma.
"There was a synergy between the two environmental factors of HPV and UVB; a single factor was not sufficient to induce disease," Dr. Tommasino says. This is different from what is seen in the development of cervical cancer and suggests a different mechanism of action, he says.
The research also suggests that while HPV38 seems to be necessary for initiating the process of lesion formation, it may be that at some point the oncogenic process takes on a life of its own and no longer needs the virus to be present in order to continue. This has implications for developing and staging prevention and therapeutic interventions, he says.