Researchers Find Gene Involved In Body's Defense Against Skin Cancer

The study is an important step towards understanding the genetic process by which non-melanoma skin cancer develops, according to Dr. Laurie Owen-Schaub, associate professor of Immunology at M. D. Anderson. Ultimately, these studies in mice may lead to new genetic screening techniques for determining the relative risk of an individual getting skin cancer after exposure to sunlight, as well as new interventions for treating the disfiguring and sometimes deadly disease, Dr. Owen-Schaub added.

"Our finding is the first to identify a protein that is a natural defense against skin cancer development which may help in finding new therapies for treating the disease," says Dr. Owen-Schaub, co-principal investigator of the research project with Dr. Laurie L. Hill.

The finding appears in the Aug. 6 issue of Science magazine published by the American Association for the Advancement of Science in Washington, D.C. The research was supported in part by the National Cancer Institute and the American Cancer Society.

Previous studies have shown that skin cancer arises as a result of DNA damage (genetic alterations) caused by ultraviolet radiation (UV) in sunlight. Until now, it has not been clear how the body normally defends itself against these genetic alterations after normal exposure to sunlight. This study has identified the defense mechanism used to remove genetic alterations in the skin. The study compared the reaction to UV radiation between two types of mice -- 20 "normal" mice with the Fas ligand protein and 20 "mutant" mice lacking the protein. The Fas ligand protein interacts with its receptor, Fas, on other cells to induce cell death.

The M. D. Anderson researchers found that mice lacking Fas ligand protein were more likely to have the genetically altered skin cells that lead to skin cancer through the failure to eliminate the damaged cells from their skin than normal mice after exposure to UV radiation. Researchers believe that the same pathway to remove genetically altered skin cells may be used in people after exposure to sunlight as other mouse studies involving Fas ligand have proven to be true in people. They emphasize that further studies are required to determine the importance of Fas ligand for protection against skin cancers in people.

Fas ligand has been implicated in a number of studies in both mice and people, including studies pertaining to rejection of transplanted organs, autoimmune diseases, and in tumor outgrowth and metastasis, Dr. Hill noted.

"This new finding suggests that Fas ligand is critically required to suppress the genetic mutations leading to skin cancer. This mechanism appears to be important to the body's natural defense against the accumulation of genetically altered skin cells induced by sunlight exposure," said Dr. Owen-Schaub. " When this defense mechanism fails or is inactivated, sunlight exposure induces the genetic alterations that then persist, eventually resulting in skin cancer outgrowth."

In one experiment, they exposed both groups of mice to 1.5 hours of UV radiation, or the equivalent for people of about 45 minutes in the sun at noon on a sunny day in Houston in August. After a laboratory analysis of the skin, they found the mice with Fas ligand had many more sunburn cells that were undergoing cell death to eliminate UV-damaged cells. On average, the 20 normal mice were found to have 65 sunburn cells, or genetically damaged cells, per linear centimeter of skin undergoing the "healthy" process of cell death and elimination. By comparison, the mutant mice lacking Fas ligand had only 18 sunburn cells per linear centimeter.

In a second experiment, they exposed 10 mice in each group to 1.5 hours of UV radiation a day for one week. They also exposed 10 mice in each group to the same amount of UV radiation a day for two weeks. Following a laboratory analysis of the skin in the experiment, they found the normal mice had significantly fewer genetically altered cells, suggesting this group of mice was doing better at eliminating UV-damaged cells. Here, on average, one in 20 (5 percent) normal mice had genetically altered cells resulting from UV exposure, compared to 14 in 20 (70 percent) mutant mice with genetically damaged cells.

An estimated one million cases of basal cell or squamous cell cancers will be diagnosed in the United States this year. These patients experience a 20 percent to 30 percent increased mortality rate from non-skin cancers. Melanoma is the most serious form of skin cancer and will be diagnosed in about 44,200 Americans this year. An estimated 9,200 individuals will die from skin cancer this year, 7,300 from melanoma and 1,900 from other skin cancers.