By David N. Leff
Glossy magazine ads and TV commercials that glamorize the virtues of suntanned bodies feature sexily clad females and males in poses that show off their golden-brown limbs and torsos. They got these done-to-a-turn physiques by disporting on Caribbean beaches or sun-lamp tanning beds and salons, or more economically by applying tanning lotions. One way or another, these browner-than-thou individuals are hinting to the world they can afford a sun-drenched lifestyle.
To indulge this tanning mystique, you don't have to go to the beach. Enough exposure to any sunny outdoor venue can enable you to acquire a suntan, or a sunburn - or for that matter, skin cancer.
"It has always been glamorous to be tan," observed immunologist Laurie Owen-Schaub. "People will do it at practically any cost. Even in spite of everything that we know about solar exposure and DNA damages in skin carcinomas, we still all want to be out there in the sun. Knowing sociologically how people behave," she went on, "I think it would behoove all of us to try to find something that we could do to at least reduce the incidence of skin cancer. Because people aren't going to give up tanning."
One paradox of this sun-worshiping lifestyle is that it can lead to premature aging and wrinkling of skin insulted by ultraviolet (UV)-ray photons. "Clearly," Owen-Schaub observed, "UV radiation does a zillion things. It turns on a lot of genes, including cytokines, which will come up and cause an inflammatory-type reaction in the skin. In sunburn, the sloughing off of dead cells - the peeling - is probably a result of apoptosis - programmed cell suicide."
Owen-Schaub, a professor of immunology at the University of Texas M.D. Anderson Cancer Center in Houston, is senior author of an article in today's Science, dated Aug. 6, 1999. Its title: "Fas ligand: A sensor for DNA damage critical in skin cancer etiology."
"As reported in our paper," she told BioWorld Today, "we have found that the protein, Fas ligand, can actually act in a protective manner to eliminate cells containing precancerous mutations, that would give rise to skin cancer. This protein, FasL, is induced upon exposure to UV light in sunlight. FasL is pretty promiscuous. It will come up, for example in response to hypoxia - oxygen deficiency - as well as to direct DNA damage. So this actually gives the cell a way to respond to its environment, and say, 'I need to be killed' - or not. It's a threshold effect. If a cell receives only a little bit of DNA damage, it will repair itself, whereas if it has excessive damage, FasL comes up, stays up, until the cell undergoes cell death, and is eliminated."
Sunburnt Skin Peels To Shed DNA-Damaged Cells
"This pathway," Owen-Schaub explained, "involves Fas ligand and its Fas receptor, which are known in other systems to induce apoptosis."
Describing the innovation in the Science paper, she pointed out, "We've not really known the molecular mechanism by which these apoptotic cells arise in the skin after UV exposure. There is a connection with the p53 tumor suppressor gene, which is also a transcriptional regulator of the Fas receptor. And p53 mutations are known to be critical genes in the development of non-melanoma skin cancer. So my colleagues and I were curious to link up those two apoptosis precursors. There was really no known molecular mechanism till then as to how these things arose."
To clear up this mystery, Owen-Schaub and her co-authors queried two strains of mice. One cohort of 20 normal, wild-type animals had all their Fas ligand marbles; the second, transgenic group of 20 lacked that apoptosis-on-switch protein. The team shaved bare the fur on the backs of the mice, and exposed them to various intensities and durations of UV radiation.
"We asked those animals two questions," she recounted. "One, in a FasL-deficient environment, would you get sunburn-cell formation? Would you be able to induce keratinocytes in the epidermis to undergo apoptosis? When we measured that, in fact it was substantially reduced in the FasL-minus mouse environment.
"Our second question was: If you fail to get normal levels of apoptosis going on after UV exposure, what are the biological consequences? The answer was accumulation of vast numbers of p53 mutations, as a result of the UV exposure given to those abnormal mice."
Honnavara Ananthaswamy, a co-author of the Science paper, Owen-Schaub related, "roughly calculated from what we learned in the mice, and based on noontime solar exposure on a sunny midsummer day in Houston, with little cloud cover, that a human will get red in 11 to 22 minutes, and incur local immune suppression in the same amount of time. That is, if you administer an antigen through that exposed skin site, you will have immune suppression. Between 22 minutes and three hours," Owen-Schaub continued, "you actually will be able to demonstrate systemic immune suppression, as a result of that exposure. And based on these calculations, after only 214 hours of cumulative exposure you would have skin cancer arising."
Many Are Burned; Few Will Die
This year in the U.S., about 1 million people will be diagnosed with basal and squamous skin cancer, a consequence of UV radiation. Although popularly regarded as benign malignancies, the disease will kill an estimated 1,900 of that number. "Those are individuals whose skin cancers are highly aggressive," Owen-Schaub said, "They are local tumors only, and while they can be extremely disfiguring, few of the patients die of the disease. The thing that kills those who do," she pointed out, "is metastasis."
But beyond that minimal mortality lurks a more sinister statistic: Those million patients who survive, she pointed out, "also experience a 20 to 30 percent increased death rate from non-skin cancers."
She and her co-authors are at present "accruing retrospective skin samples from individuals who do have skin cancer, and asking whether or not they show an abnormal response in non-sun-exposed skin. We are testing the ability of those samples to upregulate Fas and FasL after a given amount of DNA damage or of UV light.
"That connection with the 20 to 30 percent high mortality level," Owen-Schaub continued, "would suggest they may in fact have a systemic difference in their ability to handle DNA damage. Whether or not it's FasL or another pathway is really too early to say." Within the next six to nine months they propose to begin testing skin from current patients.