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Genes help spread of shape-shifting skin cancer cells

The humble fruit fly: teaching us more about melanoma skin cancer. Flickr/John Tann

Melanomas may be less common than other skin cancers but their ability to become malignant and spread to other parts of the body makes them some of the deadliest if not caught early.

More than 10,000 people in the UK are diagnosed each year and a fifth of these - more than 2,000 people - die from a malignant melanoma that has spread.

Now researchers have identified a set of genes that regulate the ability of melanoma cells to rapidly shift between two shapes, enabling them to escape from the skin and spread to other areas such as the liver, lungs and brain.

Melanomas usually start in the skin because of tumours that begin in the melocytes - responsible for producing melanin and the colour of our skin, which can lead to distinctive dark colour. It can start in normal-looking skin but also in moles.

Melanoma cells adopt different shapes to squeeze between healthy cells. A rounded shape allows them to travel through the bloodstream, but the cells then take on an elongated shape to travel through harder tissues such as bone. Until now it was not known how they changed shape or switched between the two.

Researchers at the Institute of Cancer Research and Weill Cornell Medical College in Houston, Texas, used fruit flies to investigate how the cells work. Fruit fly cells take on five different shapes as they grow. By switching off specific genes, the researchers were able to change the mix of shapes in the cells to identify several that controlled cell shape.

In melanoma cells, switching off these cells had a similar effect. Switching off one called PTEN increased the number of cells that were elongated rather than rounded.

“We think that metastatic melanoma cells lose their PTEN function so that they can increase their shape-shifting ability, which in turn enables them to move to many different tissues within the body,” Dr Chris Bakal, a Wellcome Trust research fellow at the ICR, said. “PTEN loss is common in all cancers.”

Mutations in the PTEN gene, and in some cases its absence, plays a part in the development of a number of cancers. It is switched off in one in eight people with melanoma.

“We’re implicating PTEN loss as altering shape and proliferation,” Bakal said. “Cancers normally change shape but the loss of PTEN gives them the advantage of shape shifting faster.”

“We identified PTEN but also dozens of other genes that also play a part.”

In the UK, melanoma is the most common cancer in people aged 15–34 - particularly in women - and is on the rise. UV radiation from too much sun exposure and not enough sunscreen on holiday is one of the main causes, as is the use of sunbeds. People who regularly have sunburn, especially where the skin blisters, are more at risk.

“Melanomas are dangerous because unlike most types of cancer cells they don’t follow two steps to become invasive,” Professor Dorothy Bennett, a cell biologist from St George’s, University of London, said. “As soon as they become invasive, they’re capable of metastasising [spreading to other parts of the body]. In other kinds of cancers, the cancer cells first get outside the tumour into nearby tissues, which is called becoming malignant, or invading. But they need another step before they metastasise.”

“We don’t know for sure but we believe it spreads so easily because pigment cells are migratory cells. In a human embryo, and in all mammals, pigment cells develop somewhere in the middle back before moving. They have a natural migratory trend so as soon as they’re able to divide excessively, forming a melanoma, they become dangerous.

"Another nasty feature of melanoma cells seems to be their ability to colonise almost any other area; bones and the brain for example,” she said.

“Other cancer cells usually spread to specific sites more than others. Melanomas are easy to treat if you get them early. Many are easy to cut off. Surgery is the best treatment if caught early but if it grows to 2-3mm thick it might be too late. How fast it grows depends on what kind of melanoma it is.

Surgery is the most common cure for melanoma, Mark Middleton, Professor of Experimental Medicine at Cambridge University said. Five out of six melanomas are cured by surgery. But treatment for more advanced melanomas have improved over the last three years.

"The role of PTEN varies from cancer to cancer. The absence of it in a cancer such as melanoma is very important, but not so much in bowel cancers. It has importance for brain and breast cancer. Whether it is missing or no forms one of the bases of how we classify cancer. Not having it is not necessarily a bad thing. It’s still far from clear.”

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