BioWorld International Correspondent

LONDON - Human papillomaviruses play a more direct role in the development of some types of skin cancer than previously thought, a new study showed. The findings could help researchers explain how other types of cancer spread, and eventually lead to new therapies to prevent skin cancer and metastasis.

Alan Storey, Cancer Research UK scientist at the Skin Tumour Laboratory of the Centre for Cutaneous Research in London, told BioWorld International: "Our study has provided one of the first pieces of evidence to show that human papillomaviruses can actively promote the development of skin cancer. We have found that some viruses have properties that can make them more pathogenic, and more likely to trigger cancer in skin cells."

Storey and his colleagues published an account of their work in the March 14, 2005, issue of Cancer Research, in a paper titled, "The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin."

The group has been studying what triggers non-melanoma skin cancer (NMSC). This is the most common cancer in Caucasians, with about 1 million cases in the U.S. and more than 40,000 cases each year in the UK. About one in five cases of NMSC are squamous-cell carcinomas, with most of the remainder comprising basal-cell carcinomas.

Although basal-cell carcinomas grow locally and do not usually spread, between 5 percent and 10 percent of squamous-cell carcinomas metastasize to other parts of the body. Although that rate is low, preventing the spread is a priority because so many people are affected. Storey and his colleagues have been studying the role of human papillomaviruses in the process.

The link between human papillomaviruses and cervical cancer is well established. There also have been suggestions that papillomaviruses are involved in triggering NMSC. Most recently, studies have shown that DNA from those viruses is present in the skin tumors of up to a third of NMSC in the general population.

"Over the past few years, a hypothesis has emerged that these viruses can inhibit apoptosis that normally occurs in response to exposure to ultraviolet light," Storey said. "This hypothesis holds that the viruses permit the survival of cells badly damaged by UV, thereby potentiating its mutagenic effects. But now we have shown that some viruses can actively promote skin cancer."

Instead of using a traditional model of culturing skin cells in a single layer, Storey's group has developed a model based on a system that already is well established for clinical purposes, which regenerates skin in vitro. That method involves culturing keratinocytes from adult humans on human dermis that has been repopulated with dermal fibroblasts. "This 3-D system is the closest we can get to mimicking the natural situation," Storey said.

After two weeks in culture, the cells stratify and differentiate to form an epithelium, with an epidermal layer on top and a dermal layer below, separated by a basement membrane. Those epithelial sheets are used to treat people with extensive burns.

Storey and his colleagues engineered the keratinocytes to include the gene encoding the E7 gene of human papillomavirus type 8. In normal skin, old keratinocytes eventually become the outermost layer and flake off. They are replaced from below by new keratinocytes.

"To our surprise," Storey said, "in our experiments, we saw that the keratinocytes expressing the papillomavirus E7 gene were invading downward, which meant that the basement membrane must be compromised in some way."

Further investigations showed that the proteins of the basement membrane, including collagens type IV and VII, were being progressively destroyed. Furthermore, the cultured cells were expressing higher than normal levels of enzymes called matrix metalloproteinases [MMPs], which can degrade these collagens.

"The expression of MMPs can be quite normal - as these enzymes help cells to move around the body - but tumor cells often acquire expression of MMPs, and this helps them to metastasize," Storey said.

In this case, he concluded, it seemed that the presence of the virus was turning on production of MMPs aberrantly, resulting in breakdown of the basement membrane.

The team now wants to investigate how the virus turns on the MMPs and causes the cells to invade downward. "If we can understand this process, this will suggest new strategies for intervention," Storey said. "Fortunately, much work has been done already on regulation of the MMPs, so it may be possible to work out some way of blocking these enzymes."