Findings from a study led by researchers at Dana-Farber Cancer Institute and Children's Hospital Boston have rewritten science's understanding of the process of skin tanning -- an insight that has enabled them to develop a promising way of protecting fair-skinned people from skin cancer caused by exposure to sunlight.
The study, to be published by the journal Nature in its Sept. 21 issue, involved giving tans to specially engineered mice, not by exposing them to ultraviolet rays in sunlight (the usual route to a tan), but by applying a cream that switched on the tanning machinery in their skin cells. Because people who tan easily, or have naturally dark skin, are far less likely to develop skin cancer than fair-skinned individuals -- who tend to get sunburns rather than tans -- the findings suggests that medicinally-induced tans can protect at-risk individuals from the disease.
"The study involved using a small molecule to essentially mimic the process that occurs when skin cells are struck by ultraviolet light from the sun," says the study's senior author, David E. Fisher, MD, PhD, director of the Melanoma Program at Dana-Farber and a professor in pediatrics at Children's Hospital Boston. While the compound used in the study has not yet been tested in humans, the results "demonstrate the principle that actual tanning can be 'rescued' by recognizing the normal pathway and the precise step where it is blocked in people who do not tan well," he remarks.
Melanoma is the fastest-increasing form of cancer in the world, accounting for 62,000 new cases in the United States every year and nearly 8,000 deaths, according to the American Cancer Society. It occurs when pigment-making skin cells called melanocytes begin dividing rampantly as a result of damage to their DNA. If melanoma tumors are detected and surgically removed before their cells spread to other parts of the body, patients have an almost 100 percent chance of surviving. The odds drop sharply, however, if treatment doesn't begin until the disease has spread, or metastasized.
One trigger for melanoma development appears to be ultraviolet (UV) light from the sun, which can damage the skin's DNA. For most of human history, fair-skinned people, who tan poorly, occupied regions with low sun exposure, such as Nordic areas with winter months of darkness. As human populations have scattered throughout the globe, increasing numbers of fair-skinned people have come to live in sunny climes, and melanoma and other skin cancer rates have shot up.
The new Dana-Farber report grew out of efforts by Fisher's laboratory to study melanoma in mice whose fair skin stemmed from the same genetic roots as fair-skinned people. The researchers succeeded in generating red-haired mice whose light skin contained melanocytes, but when the mice were subjected to low levels of UV radiation, they did not tan. Nor did they tan when the UV levels were raised slightly; but when they increased slightly more, the animals got skin sunburns.
"These animals couldn't tan," Fisher remarks, who is also a professor of pediatrics at Harvard Medical School. "We'd proven in a rigorous genetic system what people have known for hundreds of years: Redheads don't tan well."
This suggested that the mice were a good model for fair-skinned humans. It also led researchers to propose a new theory about how sun exposure triggers pigmentation in people who tan easily. If the researchers' theory was correct, it should be possible to induce dark pigmentation in fair-skinned mice with specific, targeted drugs.
The most common origin of red hair and pale skin in humans is found in a tiny pouch-like receptor, called MC1R, on the surface of melanocytes. When the hormone MSH -- for Melanocyte Stimulating Hormone -- drops into the pouch, it causes a surge in the melanocyte's production of the chemical cAMP. cAMP then stimulates melanocytes to turn on a large number of genes, causing a pigment called melanin to be produced. If cAMP levels are low, the melanocytes make red/blond melanin. If cAMP levels are high, they make brown/black melanin. The melanin is eventually discharged from melanocytes and taken up by keratinocytes. MC1R is shaped differently in red-haired people, so that MSH cannot stimulate it strongly. The result is that cAMP production stays at low levels. Less cAMP means less red/blond pigment production, which results in fair skin.
Many scientists have theorized that tanning occurs when ultraviolet radiation strikes the nuclei of melanocytes, causing DNA damage that prompts the melanocytes to produce pigment. This supposition, however, conflicted with the results of Fisher's experiments. "Our work suggested that a peculiarity in the MC1R receptor on melanocytes is responsible for a failure to tan," Fisher relates. "But that sort of change on the cell surface shouldn't impede UV radiation from reaching the melanocyte's DNA."
If Fisher's results were correct, the traditional picture of the biology of tanning was wrong. In a series of experiments, Fisher's team found evidence to bolster their theory, leading to a new model of how tanning occurs.
The experiments demonstrated that, rather than acting directly on the nuclei of melanocytes, UV radiation acts on keratinocytes (the most abundant as well as superficial cells in the skin), causing them to produce and secrete MSH, which attaches to adjacent melanocytes and starts the pigment-making process.
While Fisher's model adequately explains why redheads do not tan, it isn't the only possibility. "Suppose that during the embryonic or fetal period MC1R never activated cAMP production in developing melanocytes," Fisher proposes. "Would mature melanocytes then be permanently 'crippled,' unable to respond to UV, regardless of how its signals were transmitted?"
One way to disprove that "permanently crippled" scenario would be to see if melanocytes with abnormal MC1R receptors can be coaxed into producing pigment in adult mice. To attempt this, Fisher and his associates treated the skin of red-haired, fair-skinned mice with a compound known to increase cAMP levels. The compound, called forskolin, is derived from the root of the forskohlii plant found in India. The mice involved in the experiment turned dark, proving that melanocytes in redheads aren't inherently unable to make pigment if appropriately stimulated.
Further experiments showed that not only can red-haired mice be given tans without exposing them to UV light, but this sunless tanning process is virtually indistinguishable from that in dark-haired mice that tan naturally.
"When keratinocytes absorb melanin pigment, the pigment isn't randomly distributed within them," Fisher explains. "It forms arcs that look like tiny umbrellas over the keratinocyte's nucleus. When we artificially caused our red-haired mice to tan, the pigment in their keratinocytes made the exact same umbrella-like pattern."
The Dana-Farber researchers also showed that tans acquired through forskolin conferred significant protection against skin cancer caused by exposure to UV light. Fisher notes that while it is unknown whether forskolin will penetrate deeply enough in human skin to activate melanocytes, these results suggest that the search for other substances that do reach deep into the skin may well have the same pigmentation effects in people.
"These studies suggest that a drug-induced 'rescue' of the tanning mechanism may correspondingly rescue at least some aspect of skin cancer protection," Fisher observes. "Such sunless tanning may also dissuade sun-seeking behaviors, which undoubtedly contribute significantly to high skin cancer incidence."
The lead author of the study is John D'Orazio, MD, PhD, formerly a pediatric oncology fellow in Fisher's lab at Dana-Farber and Children's and now at the University of Kentucky. The co-authors include Tetsuji Nobuhisa, MD, PhD, Rutao Cui, MD, PhD, Michelle Arya, MS, Vivien Igras, and Scott Granter, MD, of Dana-Farber; Emi Nishimura, MD, PhD, of Kanazawa University, Japan; Malinda Spry of the University of Kentucky; Kazumasa Wakamatsu, PhD, and Shosuke Ito, PhD, of Fujita Health University in Japan; and Takahiro Kunisada, PhD, of Gifu University Graduate School of Medicine in Japan.
The study was supported by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, and the Japanese Ministry of Education, Culture, Sports, and Technology. Fisher is the Jan and Charles Nirenberg Fellow in Pediatric Oncology at Dana-Farber.
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