HPV, actinic keratosis genetic link allows skin cancer vaccine development

June 1, 2010

A German team is exploiting the genetic connection between actinic keratosis (AK) and the human papillomavirus (HPV) by developing an HPV-specific vaccine for Aks and invasive squamous cell carcinoma (SCC), according to a team member who spoke at MauiDerm 2010: Advances in Cosmetic and Medical Dermatology.

Key Points

Wailea, Hawaii - A German team is exploiting the genetic connection between actinic keratosis (AK) and the human papillomavirus (HPV) by developing an HPV-specific vaccine for AKs and invasive squamous cell carcinoma (SCC), according to a team member who spoke at MauiDerm 2010: Advances in Cosmetic and Medical Dermatology.

Eggert Stockfleth, M.D., professor and chairman of dermatology, Charité Hospital, Berlin, says that over the decades, exposing normal skin to chronic ultraviolet light (UV) contributes to DNA damage and downregulation of the local immune response (Nindl I, Gottschling M, Stockfleth E. Dis Markers. 2007;23(4):247-259). If the immune system cannot repair this damage, "It can bring the cell into programmed cell death, apoptosis. HPV plays a role in between those two processes," he says.

In particular, "There's not a case of cervical cancer in the world which has no relationship with the infection of oncogenic genital HPV types 16, 18, 31, 33 or 45. Cervical cancer is strongly associated with HPV," Dr. Stockfleth says.

As for the link between HPV and invasive SCC, Dr. Stockfleth says that more than 30 years ago, researchers found that special cutaneous HPV types correlate with cutaneous tumors in patients with epidermodysplasia verruciformis (EV) (Jablonska S, Dabrowski J, Jakubowicz K. Cancer Res. 1972 Mar;32(3):583-589. Orth G, Jablonska S, Favre M, et al. Proc Natl Acad Sci USA. 1978 Mar;75(3):1537-1541). These patients suffer from a downregulation of local cellular immunity, he says.

"With the combination of UV-exposed skin areas and HPV infection, 35 to 40 percent of patients with EV develop invasive cancers in those areas. This is actually the first evidence that cutaneous HPV types have something to do with skin cancer," he says.

Skin cancer, cutaneous HPV

Regarding the relationship between cutaneous HPV types and skin cancer, Dr. Stockfleth and his colleagues initially showed that 41 percent of AKs contain HPV (Meyer T, Arndt R, Christophers E, et al. Cancer Detect Prev. 2001;25(6):533-547. Meyer T, Stockfleth E. N Engl J Med. 2003 May 15;348(20):2040-2041).

However, Dr. Stockfleth says, "When you talk about HPV and DNA, you must consider the method used to detect HPV."

At the time of these studies, he explains, polymerase chain reaction (PCR) testing was not yet available. "Today, we know that in 95 percent of AKs, we have special cutaneous HPV types. And we find special cutaneous HPV types in up to 100 percent of invasive SCC," he says.

HPV types 16 and 18 occur in a total of 75 percent of cervical cancers, Dr. Stockfleth says. "The problem with cutaneous cancer is that you always can detect cutaneous HPV types, but there can be 10 different types in one lesion. The other problem was that in cutaneous cancer, the virus does not integrate into the host genome," as it does in cervical cancer, he says.

Therefore, Dr. Stockfleth and his colleagues looked for new HPV types and identified HPV 21, 5, 8, 16 and 18 as the culprit oncogenes (Nindl I, Gottschling M, Stockfleth E. Dis Markers. 2007;23(4):247-259).

"E6 and E7 are only expressed in AKs and invasive SCC," he adds, "not in normal skin or very early sun-damaged skin. That's another hint why AK is an early stage of invasive SCC. They're similar not only in terms of histology, but they also contain the same gene mutations."

When it comes to establishing persistent viral infections, he says, "Everything depends on the immune system. My clinic sees about 5,000 organ transplant patients per year." Although the normal survival rate for such patients often reaches 25 to 30 years, "The biggest problem they have is chronic skin infections and skin tumors," Dr. Stockfleth says. "Their average risk of developing invasive SCC is 200-fold higher versus the normal population."

Furthermore, he says, HPV upregulates the cell cycle in order to replicate itself. "And it downregulates apoptosis to preserve the keratinocytes in which it dwells," he says. "When you have downregulation of apoptosis, then the cell can transform potentially into a tumor. This is what we believe."

If a cell is damaged, Dr. Stockfleth says, "Tumor suppressor genes such as p53 can repair it in this stage. Or if that is not possible, they will bring it into programmed cell death. But anti-apoptotic E6 blocks these pathways and drives the cell directly into the cell cycle (Jackson S, Storey A. Oncogene. 2000 Jan 27;19(4):592-598. Giampieri S, Storey A. Br J Cancer. 2004 Jun 1;90(11):2203-2209. Giampieri S, García-Escudero R, Green J, Storey A. Oncogene. 2004 Jul 29;23(34):5864-5870)."