Study Rewrites Biology of Tanning

Could Fair-skinned People Get a Tan’s Cancer Protection Without Sun Exposure?

When the sunlight hits human skin, melanocytes in the lower layers churn out packages of melanin and deliver them to the surface cells. Eventually the melanin accumulates, forming a protective cap over the nuclei of skin cells. The result is a darkened skin tone—for some people. Fair-skinned people, particularly redheads, tend to burn rather than tan, and they also have a far higher risk of getting skin cancer. Probing the genetic differences in the skin’s reaction to sunlight has led David Fisher’s group at the Dana–Farber Cancer Institute to overturn some assumptions about the tanning process and uncover a potential therapeutic approach to give fair-skinned people the cancer protection of their darker peers.

Photo by Graham Ramsay

David Fisher (front) and John D’Orazio were tracking the steps that turn UV light into a tan when they discovered a way to activate the path chemically, sans sunlight.

Genes involved in pigmentation have been known for many years, because spontaneous mutations arising in animals are easy to spot. But science has been slow to put these genes into biochemical pathways, even the well-known process of sunlight switching on melanin. Fisher, HMS professor of pediatrics, said that his team was “trying to connect the dots, to understand the pathway that connects UV radiation to pigmentation.” In the Sept. 21 Nature, his team uses a mouse model of fair-skinned people to identify a pathway that could be manipulated to give the benefits of tanning without the sun.

Tracing the Tanning Signal
The conventional description of tanning is that UV radiation directly penetrates melanocytes in the lower layers of skin, causing DNA damage that somehow triggers the production of melanin. But using a mouse model, Fisher’s team found that the major tanning signal does not come from pigment cells, but rather the cells of the upper layers, the keratinocytes. When exposed to sunlight, keratinocytes release melanocyte-stimulating hormone (MSH), which binds to a receptor on melanocytes called Mc1r. “UV is not simply penetrating into melanocytes and inducing DNA damage—it’s an indirect pathway,” Fisher said.

Fisher’s team, with lead author John D’Orazio, now an assistant professor in pediatrics at the University of Kentucky, began this research by developing a mouse model of redheads. In humans, people with fair skin tend to have variations in the gene encoding Mc1r. But it has not been clear whether the ability to tan is directly due to that receptor. Fisher’s team first obtained mice in which Mc1r had spontaneously mutated and lost its ability to bind to MSH. These mice, indeed, have rust-colored fur and pink skin. In order to make their skin more like human skin, the team crossed the mice with another strain that expresses a growth factor that causes melanocytes to travel to the epidermis. These “humanized redhead mice” still have pale pink skin, but their melanocytes follow the pattern characteristic of humans.

Even with a layer of melanocytes in their skin, “these mice could not tan at all,” said Fisher. That finding cast doubt on the idea that UV works directly on melanocytes—since UV penetrates directly to the nucleus, such a mechanism would not be hampered by an altered receptor at the cells’ surface.

The Clinical Application
It was not clear, however, whether Mc1r was simply a broken link in a working chain in these mice or whether the Mc1r mutation caused an irreversible defect during development. As further proof that the tanning pathway was blocked at the level of the receptor, the team decided to activate a downstream target of the receptor, cyclic AMP. Many drugs are known to turn on cyclic AMP, and Fisher’s team chose one commonly available in labs, forskolin. The researchers applied the drug to the skin of the mice once a day, five days a week.

Image courtesy of John D’Orazio

Switching on a tan. Mice engineered to mimic human redheads are able to tan when treated with forskolin and are protected from UV damage. When forskolin is applied for two weeks, melanin collects in the skin cells of the mice in a characteristic capping pattern (top right), compared to controls (top left). After UV exposure, the cells of the control mice (bottom left) show more signs of damage (arrows) than those of treated mice.

The effect was clear: by two weeks, the mice were dark brown; at three, they were nearly black. “This was strongly mimicking the process of tanning,” Fisher said. The skin of the mice was filled with melanin, which even formed characteristic shells around the top of the nuclei. The pigmentation faded after treatment in the same way a UV-induced tan fades. This added pigmentation protected the skin against DNA damage from UV exposure. And when the team crossed these mice with another strain that is hypersensitive to DNA damage, mice that were artificially darkened formed tumors at a slower rate after UV exposure.

What began as proof of Mc1r’s role in tanning quickly became something that had clinical potential, “an opportunity to conceivably transfer the clinical benefit of those with dark skin to fair-skinned individuals,” Fisher said. He is currently working with a company, Magen Biosciences, that explores similar treatment strategies. Fisher said that the next step is to see whether the human tanning pathway is the same as in mice. If so, much work remains to create a drug that could effectively treat human skin, which is thicker and less penetrable than mouse skin. Finally, he said, “It’s critical to know that what we’re doing is safe.” Though the mice showed no apparent side effects from treatment, cyclic AMP is a pathway widely used in cells, and switching it on may have unexpected consequences.

Fisher emphasized that even if a product were created that could bestow a tan without sun, it wouldn’t take the place of traditional sunscreens. But its benefits could be important. Long-term data on sunscreen use has shown that it unequivocally protects against sunburn and against basal-cell and squamous-cell carcinoma. But Meenhard Herlyn, professor of molecular and cellular oncogenesis at the Wistar Institute, said, “There are no clear studies showing that sunscreen use actually prevents melanoma,” a less common but deadlier form of cancer. Although people assume that childhood sunburns correlate with melanoma risk, this relationship is not borne out in reviews of the literature. Fisher says that when looking at the risk factors for melanoma, “what screams out is the state of skin pigmentation and whether you tan easily or not.” Fair- and dark-skinned people have a hundredfold difference in risk; some research indicates that the pigment fair-skinned people produce may itself promote cancer. In a tan-obsessed culture, being able to tan without exposing the skin to harmful UV rays—while even gaining some cancer protection—could be an ideal scenario.

Herlyn said that the mice Fisher created will aid in developing treatments as well as further untangling these pathways. “The difficulty in studying much of the pigmentation pathway came from a lack of good animal models, because there is a major difference between human and animal skin,” he said. The redhead mice may help researchers clear up some of the confusion about the complicated role of UV in melanoma, a confusion that is very real to everyone who struggles with sunscreen and sunburns.

—Courtney Humphries

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