Researchers Discover Potential Skin Cancer Prevention Target

The protein, called STAT3, had been known to be involved in cancer, but John DiGiovanni Ph.D., and his colleagues showed that activated STAT3 is necessary for skin cancer to begin and that without it, skin cancer can't develop. The study, which appears in the September 1, 2004, issue of the Journal of Clinical Investigation, is the first to show STAT3's critical role in the development of skin cancer.

"This study shows STAT3 plays a role in the very earliest steps of the carcinogenic process," says DiGiovanni, the study's principal investigator and director of M. D. Anderson's Department of Carcinogenesis which is located in Smithville, about 250 miles from the Houston cancer center. "This is a bona fide target for prevention."

It is possible that one day a STAT3 inhibitor could be applied as a topical cream to treat sunburns or precancerous lesions to prevent progression to cancer, he says.

Signal transducers and activators of transcription 3 (STAT3) belong to a class of proteins called transcription factors that can lead to cancer by allowing a healthy cell to respond inappropriately to external signals to divide. Transcription factors are potent proteins because they set off a cascade of events by activating numerous genes, which in turn lead to the production of growth-promoting proteins. Activated STATs have been observed in a wide variety of human cancers, including lymphomas and solid tumors. Because of its newly discovered role in the initiation and promotion stages of skin cancer, intensive effort should now be focused on researching the proteins activated by STAT3, DiGiovanni said.

The researchers became interested in the role of STAT3 when they learned it had been linked to wound healing, a process that shares many of the same features with the process of tumor promotion. Initial studies in DiGiovanni's lab showed that chemicals known to promote skin cancer also activated STAT3.

To further study the role of STAT3 in skin, the scientists used mice in which STAT3 was missing in skin cells. These mice did not get skin cancer after treatment with a known cancer-causing agent, while mice with normal levels of STAT3 developed numerous skin tumors. Without STAT3, most of the damaged skin cells simply died, while those that survived could undergo proliferation which is necessary for the earliest stages of cancer development.

To further explore the importance of STAT3 in skin cancer, the scientists injected a small piece of DNA called an oligonucleotide, into skin tumors of normal mice. The oligonucleotide was designed to bind STAT3 and prevent it from activating genes. In this experiment, half of the skin tumors injected shrank by more than 60 percent.

"We discovered that STAT3 is a unique molecule that regulates critical sets of genes involved in the initiation and promotion of cancer," says DiGiovanni. "Furthermore, we have evidence that if you block the action of STAT3, you get tumors that regress. This makes STAT3 an attractive target for both treatment and prevention of skin cancer."

DiGiovanni's collaborators included graduate student Keith Chan, Shigetoshi Sano, M.D., and Kaoru Kiguchi , M.D., of M. D. Anderson; Joanne Anders, National Cancer Institute, Bethesda, Md.; and Nobuyasu Komazawa, M.D. and Junji Takeda, M.D.; Osaka University Graduate School of Medicine, Osaka, Japan.

The study was funded by grants from the National Institutes of Health, the National Institute of Environmental Health Sciences and a M. D. Anderson Cancer Center Support Grant.