Student guest post by Desiré Christensen
Human papillomaviruses (HPVs) are small DNA viruses that infect epithelial cells. There are well over 100 subtypes of HPV. The subtypes that infect cutaneous epithelia are termed beta-HPVs and those that infect the mucosal epithelia are termed alpha-HPVs. Some alpha-HPVs have received attention as strong risk factors for the development of cervical cancer. Less public awareness has been generated over the role of HPVs in the development of other cancers such as vulvar, vaginal, anal, head and neck, and penile cancers. Only recent research has focused on an association between HPV infection and skin cancer development.
Infection with beta-HPVs and development of skin cancer was first identified in patients with a rare inherited disorder called epidermodysplasia verruciformis (EV)(1). Roughly 50 percent of EV patients develop premalignant skin lesions and squamous cell carcinomas (SCCs) by the time they are 40 (2). Lesions and carcinomas mainly develop in sun-exposed regions, but HPV DNA has also been detected.3 Based on these findings, an interactive carcinogenesis between HPV and UV radiation has been suggested.
Immunocompromised patients are at increased risk of developing SCCs and other skin lesions, supporting the hypothesis that an infectious agent may play a role in skin cancer development. Organ-transplant recipients are at increased risk of developing warts and other skin lesions often followed by the development of SCC. The prevalence of beta-HPV DNA nears 100 percent in premalignant lesions and SCC in these immunocompromised individuals (4,5). In comparison, beta-HPVs have been detected in 30 to 60 percent of SCCs from immunocompetent patients (6).
A study by Karagas et al (7) aimed to describe the association between beta-HPVs and squamous cell carcinomas by testing for anti-HPV antibodies. Anti-HPV antibodies were found 60 percent more often in cases of squamous cell carcinomas compared to controls. A significant association between basal cell carcinoma and beta-HPVs was not observed. Beta-HPVs were associated with squamous cell carcinomas even after adjusting for smoking, drinking, medical and family history, and sun exposure (7).
Mechanisms for the role of HPVs in skin cancer are currently under investigation.
Recent research supports the biologic plausibility of a causal pathway from HPV infection to the development of skin cancer. The E6 and E7 proteins in high-risk types of HPV are known to modify and interact with cellular proteins leading to uncontrolled cell growth. In response to UV damage, the E6 protein from several beta-HPVs effectively inhibits cell apoptosis (8). The promoter of beta-HPV types 5 and 8 is also stimulated by UV exposure (9). Disruption of UV-induced thymine dimer repair has been demonstrated in cells expressing beta-HPV type 5 E6 protein, but has not been shown in cells expressing the E6 protein from other beta-HPVs (10).
The interaction between E6 and Bak, a proapoptotic effector, has been studied as a possible oncogenic pathway. Bak is degraded by the beta-HPV E6 protein resulting in protection from apoptosis in UV damaged cells. The degradation of Bak by beta-HPVs can occur without affecting regulators of Bak. The ability of the E6 protein to degrade Bak was not different between beta-HPV subtypes, suggesting other mechanisms should be studied to explain differential carcinogenesis (11).
More mechanistic studies are needed to determine the carcinogenic properties of beta-HPVs and their potential role in skin cancer development. More epidemiologic studies are needed to determine causality. Most studies have demonstrated an association between beta-HPVs and skin cancer through detection of HPV antibodies or DNA in cancer tissue and the sample sizes used have been small. The presence of HPVs in cancer tissue encourages further investigation but does not prove causation.
UV exposure is known to be a strong risk factor for the development of skin cancer, but recent research has indicated a potential role of HPV infection in skin cancer. It is possible that HPV interacts with UV exposure in oncogenic pathways. There is increasing evidence supporting the biologic plausibility of an interactive effect. Beta-HPVs are ubiquitous in the population and present in both normal and cancer tissues, making it difficult to conduct a prospective study. HPV detection methods have improved over time and should be combined with a strong epidemiologic study design to demonstrate causation (6).
1. Lutzner, M. A., C. Blanchet-Bardon, and G. Orth. (1984) Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dermatol 83:18-25
2. Orth, G., S. Jablonska, M. Jarzabek-Chorzelska, S. Obalek, G. Rzesa, M. Favre, and O. Croissant. (1979) Characteristics of the lesions and risk of malignant conversion associated with the type of human papillomavirus involved in epidermodysplasia verruciformis. Cancer Res 39: 1074-82
3. Pfister, H. (1992) Human papillomaviruses and skin cancer. Semin Cancer Biol 3:263-71
4. Bouwes Bavinck JN, Plasmeijer EI, Feltkamp MC. (2008) Beta-papilloma- virus infection and skin cancer. J Invest Dermatol 128:1355-8
5. Pfister H. (2003) Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31:52-6.
6. Asgari MM, Kiviat NB, Critchlow CW, Stern JE, Argenyi ZB, Raugi GJ et al. (2008) Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. J Invest Dermatol 128:1409-1417
7. Karagas MR, Nelson HH, Sehr P, Waterboer T, Stukel TA, Andrew A et al. (2006) Human Papillomavirus Infection and Incidence of Squamous Cell and Basal Cell Carcinomas of the Skin Journal of the National Cancer Institute 98:389-395
8. Jackson, S., and A. Storey. (2000) E6 proteins from diverse cutaneous HPV types inhibit apoptosis in response to UV damage. Oncogene 19:592-8
9. Akgul, B., W. Lemme, R. Garcia-Escudero, A. Storey, and H. J. Pfister. (2005) UV-B irradiation stimulates the promoter activity of the high- risk, cutaneous human papillomavirus 5 and 8 in primary keratinocytes. Arch Virol 150:145-51
10. Giampieri, S., and A. Storey. 2004. Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18. Br J Cancer 90:2203-9
11. Underbrink MP, Howie HL, Bedard KM, Koop JI, and Galloway DA. (2008) The E6 proteins from multiple beta HPV types degrade Bak and protect keratinocytes from apoptosis after UVB irratiation. J Virol 82:10408-17