February 7, 2011

How UV Radiation Triggers Melanoma

Electron micrograph of a round cell with stringy filaments on its surface A human melanoma cell grown in culture. Anne Weston, LRI, CRUK, all rights reserved by Wellcome Images.

A protein that immune cells use to communicate with each other is involved in the development of melanoma, a new study shows. The findings offer fresh insight into how melanoma may develop in some patients and suggest a new potential target for treatment.

Melanoma is an aggressive skin cancer that often resists drug treatment. It arises when pigment-producing skin cells, called melanocytes, become cancerous. Unfortunately, melanoma is becoming more common every year.

Studies have shown that exposure to ultraviolet (UV) radiation from the sun increases your risk of getting melanoma, especially if you had sunburns during childhood. Over the last several years, a team of scientists has used genetically engineered mice to confirm the link between UV and melanoma. The team, including Dr. Glenn Merlino and Dr. M. Raza Zaidi of NIH’s National Cancer Institute (NCI), has recently been working to decipher the nature of that link.

In the current study, published online in Nature on January 19, 2011, the researchers set out to determine what changes take place when melanocytes are exposed to UV radiation. The scientists developed mice whose melanocytes expressed a green fluorescent protein. The cells could then be easily tracked in the mouse and purified from the skin.

The team exposed the mice to levels of UV radiation that would normally cause sunburn in people. They saw greater numbers of melanocytes in the skin afterward, and the cells migrated toward the outer skin layer. Analysis of the cells showed that they expressed a set of genes known to respond to a protein called interferon-gamma (IFN-g). These changes did not occur when the researchers blocked IFN-g in the mice, suggesting that this protein is involved in activating melanocytes upon exposure to UV radiation. The finding is surprising because IFN-g had previously been thought to contribute to the body’s defenses against cancer.

The scientists figured out that the IFN-g came from immune cells called macrophages, which entered the skin upon UV exposure. When the team mixed these UV-elicited macrophages with melanoma cells and transplanted them into mouse skin, they saw increased growth of tumors. However, macrophages taken from mice that hadn’t been exposed to UV didn’t promote tumor growth. The increased tumor growth also disappeared when the researchers blocked IFN-g.

Finally, the team looked at human melanoma tumors. They found that 70% of them contained macrophages producing IFN-g. Taken together, these findings strongly suggest that IFN-g-producing macrophages play a substantial role in promoting UV-induced melanoma. Therefore, treatments that block IFN-g after sunburn might prevent melanocytes from becoming cancerous.

"We anticipate that this discovery may change how interferons are used in the clinic as anticancer agents," says Merlino. "If applicable to humans, our findings raise the possibility that targeting the IFN-g pathway may represent a novel, less toxic therapeutic alternative for effective treatment of a subset of malignant melanoma patients, who currently have poor cure rates."

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