UNRAVELLING THE PATHWAY IN SKIN CANCER DEVELOPMENT

Cancer Research UK funded scientists, at The Institute of Cancer Research, have unravelled the role of a gene important in the development of the deadliest form of skin cancer, malignant melanoma, a study published in the Journal of Cell Biology reveals today*.

The team found that a damaged version of a gene called B-RAF blocks an important pathway involved in preventing the growth of cancer cells. 

By regulating the relationship between the B-RAF protein and the pathway in human cells and animal models, the researchers were able to significantly slow cell growth.  This could lead to improved treatments for skin cancer in the future.

Most skin cancers are caused by damage to genes by UV (ultraviolet) rays in sunlight.  When cells become damaged, they can start to divide uncontrollably which can lead to the onset of cancer.

The B-RAF gene is damaged in around 7 out of 10 melanomas, and is one of the earliest events leading to skin cancer.  However, B-RAF is essential for healthy cells to function, so completely eliminating this gene is not a simple treatment option.

The researchers found that when the B-RAF gene is damaged, it suppresses the production of another protein called MITF.  MITF blocks melanoma cell division, so consequently when B-RAF is damaged, tumours develop more easily.

When the researchers artificially increased MITF protein levels in human and animal models with a faulty B-RAF gene, the growth of melanoma cells was suppressed by between 73% and 84%.

Dr Richard Marais, from the Cancer Research UK Centre for Cell and Molecular Biology at The Institute of Cancer Research, explains: "Regulating the relationship between B-RAF and MITF is a bit like controlling a car, you have to find the right balance to keep it moving.  B-RAF enables the car to accelerate, but it also removes an essential brake, MITF, which allows cells to become cancerous.       

"This research helps us to understand more about the complicated journey that is melanoma development.  The next stage will be to investigate how B-RAF controls MITF.   We hope that furthering our understanding of the behaviour of cells will, in the future, give patients a clearer idea of the stage of their disease, and allow for personalised drugs to be developed based on this."

Professor John Toy, Cancer Research's Medical Director, says: "With melanoma cancer rates set to treble over the next thirty years, it becomes ever more urgent that new therapies are developed to treat the disease.  Understanding how cancers form and grow out of control is an important part of finding new and better cancer treatments.

It's important to remember that roughly four out of five cases of skin cancer are preventable with up to 80 per cent of malignant melanomas of the skin in the UK being caused by excess exposure to the sun.  In addition to funding basic research such as reported here, Cancer Research UK is committed to promoting sun protection messages through its SunSmart campaign, which encourages everyone to take care in the summer sun, especially those people with fair skin who burn easily."

* Elevated expression of MITF counteracts B-RAF–stimulated melanocyte and melanoma cell proliferation.  Claudia Wellbrock and Richard Marais.  Journal of Cell Biology.  Volume 170, Issue 5, Pages 703-708.

Skin cancer is very strongly linked to ultra violet radiation (UVR) exposure.  UVR is invisible and cannot be felt on the skin.  It penetrates skin cells, causing damage than can lead to sunburn, skin ageing, DNA damage and skin cancer.  There are three types of UVR, but only two reach the earth’s surface, UVA and UVB.  UVC is filtered out by the ozone layer. 

UVA is responsible for skin ageing and is also likely to cause skin cancer.

UVB causes redness and sunburn.  Exposure to UVB is a major risk factor for all types of skin cancer.

Cancer Research UK 's Sunsmart campaign suggests the following for taking care in the sun:

        Stay in the shade between 11am-3pm

        Make sure you never burn

        Always cover up with a T-shirt, wide brimmed hat and sunglasses

        Remember to take extra care with children

        Then use factor 15 plus sunscreen

Also report any mole changes or unusual skin growths promptly to your GP.

Nine out of ten skin cancers are easily treatable and unlikely to spread. They are called non-melanoma skin cancer and there are more than 60,000 new cases registered each year in the UK .

Malignant melanoma, which accounts for almost one in ten skin cancers, is the most serious type of the disease and may be fatal.

Over 7,000 people a year in the UK are diagnosed with malignant melanoma. It usually develops in cells in the outer layer of the skin but can spread to other parts of the body.

The Sun Smart campaign is funded by UK Health Departments and launched in March 2003. Members of its advisory board include representatives of the Health Protection Authority (Radiation Protection Division), British Association of Dermatologists, International Commission on Non-Ionising Radiation Protection, EUROSKIN, UK Skin Cancer Working Party, British Photodermatology Group, Wessex Cancer Trust and, more recently, independent experts on vitamin D and nutrition. Boots, Homebase and BAA are also backing the campaign.

For more information about the Sun Smart campaign, visit www.sunsmart.org.uk  

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CRUCIAL GENE IS THE KEY TO SKIN CANCER

A SINGLE gene may play a major role in nearly all cases of the most commonly diagnosed human cancer, according to a report published today (Saturday)*.

Scientists funded by Cancer Research UK and the Association for International Cancer Research (AICR) have shown that cells in over 90 per cent of basal cell carcinomas (BCC), the commonest form of skin cancer, have genetic damage in the same place.  They have pinpointed the location to an area of the genome that contains ˜Patched" (PTCH), a gene already known to be involved in skin and other types of cancer.  Genetic damage is caused by UV waves present in sunlight. 

But the team, based at Barts and The London, Queen Mary's School of Medicine and Dentistry, now suggest that PTCH is the first hit in a chain of events that leads to BCC, and is, therefore, essential to the development of the disease.

Basal cell carcinoma is the most common form of cancer, affecting tens of thousands of people each year in the UK **. Although most people who develop BCC survive the disease, it can be particularly difficult to cope with.  Because it tends to affect areas of the skin exposed to sunlight, such as the face, treatment often leaves highly visible scars or damaged features.

The PTCH gene has been implicated in BCC before, but previous studies were unable to show the full extent of its importance. This study used new technology to pick up the genetic differences between BCC cells and the patients healthy cells in much greater detail.

Lead researcher, Professor David Kelsell, says: We used a technology called a gene chip array that detects any difference between two sets of genes. It's a vast improvement on previous technologies, which could not pick up certain differences. By comparing a BCC patient's tumour cells with their healthy cells, we were able to see all of the genetic events that played a part in the development of disease in that individual.

In about 90 per cent of patients, there was a genetic difference in the same area on chromosome 9 the location of a number of genes, including the PTCH gene. This means it's extremely likely the same genetic changes are involved in the majority of cases.  As 70 per cent of these tumours were found to have mutations in the PTCH gene, we think this gene is probably the ˜first hit in the development of most BCC.

Dr Muy-Teck Teh, lead author, says: ˜signature fingerprint for BCC has been identified, which has very few genetic changes compared to that seen in non-skin epithelial cancers like breast and colon.  Though PTCH is the major gene in BCCs, other genes may play additional roles in BCC development.  Our current studies are trying to find out how mutations in PTCH can lead to the development of this common skin tumour.

Dr Mark Matfield, AICR's Scottish scientific consultant says: "There are over two hundred different types of cancer and each one is caused by a handful of key genetic changes.  This new gene-testing technology means we will be able to identify them all and that means we can soon start developing treatments aimed at the actual cause of the cancers.  What Professor Kelsell and his colleagues have discovered for skin cancer will, we expect, be followed by similar discoveries on many different types of cancer, pushing the study of cancer into the next stage of genetic research."

Professor John Toy, Cancer Research UK's Medical Director, says: The interesting thing about this research is that it suggests a single gene plays an integral role in nearly all cases of BCC.   Unravelling how mutations in PTCH play a role in causing this common cancer will provide yet further insights into how cancers arise.  But avoiding excess sun exposure will remain the priority in preventing skin cancer.

   (21/9/05) and (1/10/05)