The Darker Side of Sunlight

The threat of melanoma is not to be taken lightly.

By Kathleen Kocks

Humans are naturally drawn to the comfort of a sunny day. But according to a new discovery by two GW research professors, there is one more reason to avoid basking in the sun.

In a paper published in the September 2001 edition of Nature and in the September 2004 journal Cancer Research, the husband-and-wife team of Edward C. De Fabo and Frances P. Noonan identified ultraviolet B light as the waveband active in initiating cutaneous malignant melanoma, the most aggressive and most lethal form of skin cancer. Additionally, the pair determined that UVB exposure at an early age was critical in initiating melanoma.

The paper, titled “Ultraviolet B but not Ultraviolet A Radiation Initiates Melanoma,” also reported that ultraviolet A light had no role in initiating melanoma, even at relatively high doses. Furthermore, data seemed to indicate that UVA light might even inhibit the growth of melanoma tumors.

Scientists have long suspected that UVB, the light that causes sunburn, had a role in causing melanoma. But until this study, no one had assessed the individual roles of UVB and UVA in inducing melanoma in mammalian skin.

“There is somewhat of a controversy about UVA’s role in human melanoma. For one reason, UVA is more prevalent; the ratio of UVA to UVB in sunlight is about 20:1,” De Fabo says. “But because we have a unique light system which produced defined UVA or UVB and a unique mouse model which strongly recapitulated human disease, we feel very confident in our conclusion that UVB is the major waveband for the initiation of melanoma.”

For their research, De Fabo and Noonan collaborated with Thomas Fears and Glenn Merlino, both of the National Cancer Institute. The researchers employed sunlamps, and a unique GW-developed light system that produces isolated UVB or UVA wavebands or solar-simulating radiation that includes UVB, UVA, and visible light in proportions approximating sunlight. For their animal model, they used the first transgenic mice that, in response to UV, produce melanomas that resemble human melanoma.

“Our transgenic mouse was developed by our collaborator at NIH [National Institutes of Health], Dr. Glenn Merlino, who was studying a hepatocyte growth factor. He genetically engineered the mice so that this growth factor was overexpressed throughout the mouse,” Noonan says. “To his surprise, the resulting mouse had melanocytes, pigment cells, throughout its skin, rather than only in its hair follicles. Thus, the mouse skin was much more like human skin. If he kept the mice until they were very old, they started getting melanomas, but these melanomas were not comparable to the tumors of human melanoma.”

De Fabo and Noonan’s unique GW-developed light system, shown here with samples of paper for demonstration purposes, serves as a “solar simulator,” producing UVB, UVA, and visible light in proportions that approximate sunlight. The unique system allows the production of many different narrow wavelengths, or colors, of different shades throughout the ultraviolet part of the spectrum and allows an exact shade to be spread across a wide exposure field. It is a process that was not previously available with other instruments. Julie Woodford

“We obtained some of these mice around 2001 and started irradiating them with ultraviolet light as adults, at about six weeks old, but they made no melanoma skin cancer. We then looked at the literature on the epidemiology of melanoma and found that if a person gets sun exposure as a child, they are more likely to get melanoma. So we began UV-irradiating the mice as babies, about three days old and, several months later, they developed melanoma,” Noonan says. “These melanomas closely resembled human melanomas.”

To determine which UV waveband played the greatest role in melanoma initiation, De Fabo and Noonan began irradiating the infant mice with UVB only, UVA only, or a combination of both. Comparing the data, UVB showed a significant positive trend for initiating melanoma, whereas UVA showed a negative, but not significantly negative trend.

It required surprisingly little radiation to initiate melanoma. The exposure lasted only 15 minutes and the dose given was equivalent to being exposed to two hours, 40 minutes of sunlight on July 4, 2000, in San Diego. The mice were also irradiated with a much lower dose of UVB (about a third less), and even this dose was very effective in producing melanoma; five of 10 treated mice developed melanomas.

This study is not the first to produce significant discoveries by De Fabo and Noonan, who perform their research at the Laboratory of Photobiology and Photoimmunology at the GW Medical Center. Combining De Fabo’s expertise in photobiology and Noonan’s expertise in immunology, the pair began their research in the 1980s as one of the first groups to study the role of UV in human health problems. Their first discovery revealed the mechanism of how UV light suppresses the immune system.

“Through our work, we came across urocanic acid on human skin. At the time, the acid was known only to absorb UV light,” De Fabo says. This led to an assumption that it prevented UV light from penetrating beyond the skin surface and thus offered a level of UV protection. Some sunscreen manufacturers even included urocanic acid in their formulas and advertised it as a UV blocker.

De Fabo and Noonan discovered that urocanic acid had a far different role. When urocanic acid absorbs UV, it is altered—it isomerizes or “bends”—and it sends a signal to the spleen and lymph nodes that reprograms immune system cells from being attacker cells to being suppressor cells. Urocanic acid was removed from sunscreens and cosmetics following De Fabo and Noonan’s reporting of its immunosuppressive effects.

“Why would nature select a biological process that would allow tumors to grow and be harmful to the host? One possibility is that when the skin is exposed to sunlight and burns, the skin cells look foreign and the immune system normally would attack them. The urocanic acid tells the attacking army to stop, so the skin can heal. But while the immune system is suppressed, skin cancers or tumors can form and grow. If all things were working the way they should, the immune system would destroy the skin tumor right away,” De Fabo explains.

In 1983, the researchers published a paper, “Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for existence of a unique photoreceptor in skin and its role in photoimmunology” in the Journal of Experimental Medicine. This paper earned De Fabo and Noonan international recognition.

De Fabo and Noonan’s recent paper on UVB’s role in initiating melanoma is also gathering accolades. The Faculty of 1000, a group of scientists that regularly reviews medical papers, rated it as excellent, its top rating.

What’s next for this research duo? “We are seeking a grant to do an action spectrum that would use different wavelengths within the UV bands, to see how effective they are for initiating melanoma. We would also explore how various compounds in the skin absorb different wavelengths of UV light. If we can determine the compound that absorbs melanoma-producing wavelengths, we would have a very powerful tool for identifying the currently unknown photoreceptor that initiates melanoma. When we know what that molecule is, we can do all kinds of things, like design better sunscreens or design a personal dosimeter that tells you when you are approaching melanoma-producing overexposure to UV light,” De Fabo says.

“It’s not your run-of-the-mill approach to disease study, because most people don’t take light into consideration. But we now have collaborators in the molecular area, particularly at NIH, who are studying with us how different wavelengths of light can activate various molecular genetic pathways that regulate cell activity.”

Looking at other research paths, Noonan says, “Now that we have this mouse model, we could breed mice that have other genetic changes, so we could maybe explore how to repair DNA damage from UVB or look at other genetic susceptibility factors involved in the incidence of melanoma. Everyone who is sunburned doesn’t get melanoma; it is the combination of light and genetic susceptibilities. We would like to know what they are.”

Meanwhile, De Fabo and Noonan feel it is imperative to stress the need to avoid overexposure to UV light.

Julie Woodford

“We know that fair-skinned people who move to places like Australia, where there is more UV light, get more skin cancer,” Noonan says. “It’s not a far stretch to say if we get more UV everywhere, then we will get more skin cancer. We truly need to protect our children from sunburn, particularly during the first 12 years. The parameters from our research showed us that you might need only a couple of bad burns to initiate melanoma later in life.”

De Fabo agrees, particularly about the probability of more UV exposure. His sentiment is based on his UV research, as well as his research since the 1980s as a member of many scientific committees studying global warming and the Earth’s compromised ozone layer. For his contributions, De Fabo won in 1997 a United Nations Environmental Program Ozone Award. He was also one of 300 scientists who conducted a multiyear study of dramatic global warming and ozone layer thinning in the Arctic; a much publicized report on the topic was issued in November 2004.

“If ozone depletion is continuing and, make no mistake it is, then we can expect increased exposure to and danger from ultraviolet B radiation,” De Fabo says. “We are seeing melanoma in younger and younger people, and the incidence of melanoma in the United States has doubled in the past 25 years. It is a very aggressive disease. Don’t ask for trouble by staying out in the sun unprotected, especially with children or if you have predisposing conditions.

“We slather our kids with sunscreens and think it is OK for them to be outside, but sunscreens may not protect them 100 percent, especially from UV immuno-suppression. Just avoid overexposure to sunlight, particularly the two hours before and the two hours after noon. That’s the time when your kids should be inside.”

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