NIH study in mice uncovers pathway critical for UV-induced melanoma

Researchers at the NCI reported today in Nature that interferon-gamma, a protein that had been thought to contribute to an innate defense system against cancer, may in some circumstances promote melanoma and incite the development of tumors. This finding was the result of a series of experiments designed to understand how solar UV radiation causes melanoma. Cutaneous melanoma is a highly aggressive and frequently drug-resistant cancer with rising incidence rates. The major environmental risk factor for the disease is UV radiation exposure, usually from the sun, and the highest risk is associated with intermittent burning doses, especially during childhood.

According to this group of researchers-led by Glenn Merlino in the Laboratory of Cancer Biology and Genetics at the NCI and research fellow and first author M. Raza Zaidi-the results of this study offer the possibility that the inhibition of interferon-gamma immediately after sunburn might block the carcinogenic activation of melanocytes, the skin’s pigment-producing cells, possibly making this an effective preventive strategy against UV radiation-induced melanoma.

Of crucial importance to these experiments was the development of a genetically engineered mouse in which the melanocytes were labeled with a green fluorescent protein. The tags allowed for the visual tracking and isolation of the melanocytes and enabled researchers to evaluate, for the first time, the response of melanocytes to UV radiation exposure while in their natural environment.

The researchers observed that UV radiation doses equivalent to what would cause sunburn in human skin resulted in increased numbers and movement of melanocytes in the mouse skin. An analysis of gene expression changes associated with the melanocyte activation revealed the abnormal expression of a number of genes known to be responsive to interferon-gamma. When the function of interferon-gamma was inhibited at the time of UV radiation, the number of melanocytes and their movement remained normal, suggesting that interferon-gamma was responsible for the UV radiation-induced activation of the melanocytes.

The source of interferon-gamma within the skin was determined to be macrophages-cells that normally protect against infection-that had infiltrated the skin after UV exposure. Macrophages were shown to initiate melanoma when transplanted under the skin of mice; however, this effect was prevented when interferon-gamma was blocked. Moreover, when the scientists examined human melanoma tissue samples, they found interferon-gamma-producing macrophages in 70 percent of the tumors, supporting the idea that these macrophages can significantly contribute to the initiation and/or progression of melanoma in humans.

"We anticipate that this discovery may change how interferons are used in the clinic as anticancer agents," said Merlino. “Our findings raise the possibility that targeting the interferon-gamma pathway may represent a novel, less toxic therapeutic alternative for effective treatment of malignant melanoma patients, who currently have poor cure rates.”

These studies were made possible through long-term collaborations with Edward De Fabo, Ph.D., and Frances Noonan, Ph.D., of George Washington University Medical Center, Washington, D.C.