A ray of hope for sun worshippers

Skin cancer is on the increase, but our knowledge and understanding of the disease are also growing. Ruth McKernan reports It seems that unsightly peeling is good for us
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The Independent Online
Searching out the winter sun on the ski slopes or the beaches of the Caribbean has its price. Along with a healthy-looking tan comes the unhealthy risk of skin cancer.

The British are particularly susceptible - notably those who tan poorly and are of Celtic descent, with fair or red hair and blue or green eyes. They can fall victim to three types of skin cancer. The less serious types, basal cell carcinoma and squamouscell carcinoma, account for 100 new cases each year per 100,000 people. When caught early, these types are eminently treatable and curable, says Professor Rona MacKie, of the Department of Dermatology at the University of Glasgow.

The third type, malignant melanoma, is more serious. It accounts for 10 new cases a year per 100,000 people and is responsible for the majority of deaths from skin cancer. All forms are on the increase, but the biggest increase has been in cases of malignant melanoma. "The numbers of malignant melanoma have doubled in the past 10 years," says Professor MacKie.

But there is hope: scientists are making progress in understanding how cells deal with the perpetual risk of damage from the Sun's ultraviolet light and how the failure of these processes can lead to melanoma.

Exposure to UV light (or some toxic chemicals) damages DNA. Most frequently sunlight welds together two of the millions of sub-units that make up the molecule of heredity. This prevents DNA from being copied normally, just as the instructions of a manualwould be misread if two pages were stuck together. Fortunately, a cell has all the necessary equipment to correct the damage. Specialised enzymes can cut out the fused units and replace them with normal ones. These enzymes were last month named "Molecules of the year" by the American journal Science.

It is vital that defective DNA is repaired quickly before a faulty copy is made. "If cells divide when they are abnormal, the chances of getting cancer are much greater," says Professor MacKie.

One gene in particular, called p53, plays a crucial role in controlling the performance of many cells in our body in much the same way that a referee controls a football match. A referee can blow his whistle and stop the game when he spots a foul. Then he may allow a trainer on to the pitch to treat an injured player; or he may send a man off if his behaviour is unacceptable. The overall effect is to slow the game down and ensure fair play and minimal disruption.

Dr David Lane from the Cancer Research Campaign Laboratories at the University of Dundee first proposed that p53 can perform a similar role in the cell to avoid permanent damage two years ago. By policing the cell, it suppresses the development of tumours. When the DNA is damaged, p53 - acting as the referee - temporarily halts the normal cycle of cell growth and development, allowing time for patrolling teams of enzymes to repair the damage.

In its pivotal role, p53 regulates the actions of many other supporting genes, in the same way as a referee can call on the trainers from the bench. Some of the support genes have recently been identified.

At the end of last year, a group of American researchers led by Albert Fornace, Professor of Molecular Biology at the National Cancer Institute in Maryland, claimed to have found the cell's equivalent of the trainer who brings on the magic sponge to put an injured player back in the game. They found that p53 doesn't just slow down cell growth, it also directly stimulates the DNA repair machinery via a second gene, known as GADD45 (growth-arrest-and-DNA-damage-inducible).

In some cases the cell adopts a more severe strategy to deal with damage. p53 can trigger the cell to commit suicide, although scientists do not fully understand what dictates the suicide or repair option. This process, called apoptosis, removes damaged cells in a carefully controlled manner analogous to sending a player off the pitch. Putting the cell on hold while DNA is mended, has earned p53 the title "guardian of the genome". For initiating cell death it has also, more recently, been dubbe d "guardian of the tissue."

Mutations in DNA are routinely corrected by p53's swift action, but if the mutation occurs in the p53 gene itself, then this can lead to cancer. But then with a bad referee, all hell can break loose on the football pitch.

Over the past 10 years, scientists have found mutations in the p53 gene in many of the most common cancers including breast cancer and colorectal cancers. In Nature, last month, Douglas Brash, Professor of Genetics at Yale University School of Medicine in Connecticut, and his team reported that they had analysed 45 samples of pre-cancerous skin and discovered that nearly two-thirds had mutations in their p53 genes, indicating that such alterations are an early event in the development of skin cancer.

Skin cancer is increasing because more UV light is reaching us through the thinning ozone layer and people are sunbathing more. Professor Brash's theory explains how repeated exposure to UV light causes skin cancer.

"You can think of it in terms of three trips to the beach," he says. "The first time your skin is damaged by sunlight most cells are able to repair the damage and if not they self destruct." The p53 gene is in control, so the skin recovers or undergoes apoptosis, recognisable as the pink sunburn which adds colour to British bodies on beaches around the world. So it seems that unsightly peeling is good for us. It is a deliberate attempt by the skin to get rid of damaged cells.

"The second time you go the the beach the UV light might also induce mutations in DNA, sometimes in the p53 gene," says Professor Brash. This can happen at many different sites on the skin and each mutation is a potential problem.

"On the third trip to the beach the skin gets burnt and most damaged cells die as they should. Those with a mutation in p53 don't die but multiply abnormally." Gradually, cells with a defective p53 accumulate and these abnormal cells replace those lost by programmed cell death. Losing surrounding cells gives the mutants room to grow out of control and the potential to become cancerous.

There are frequently mutations in the p53 gene in many common cancers, including breast and colorectal cancers. "Mutations in p53 are more common in skin cancers than other types: 90 per cent of squamous cell carcinoma and 60 per cent of basal cell carcinoma have mutations," says Professor Brash.

Not all mutations in p53 lead to cancer. Other failsafe procedures come into play and rescue pre-cancerous cells. The control of normal cell development is complicated. When it comes to working out what all the players do, "the field is still a little murky", he says.

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