BioWorld International Correspondent

LONDON - A molecule that controls the growth of pigment-producing skin cells called melanocytes could hold clues to new therapies to treat malignant melanoma. Researchers in the UK have established that the molecule, called MITF, can suppress the growth of malignant melanoma cells in a laboratory model of the disease.

Richard Marais, team leader at the Cancer Research UK Centre for Cell and Molecular Biology at The Institute of Cancer Research in London, told BioWorld International: "We now have a greater understanding of the processes that convert melanocytes into malignant melanoma cells. This will allow us to identify new therapeutic targets, in order to develop new drugs to treat this disease."

Most skin cancers are easily treatable and unlikely to spread. By contrast, malignant melanoma, which accounts in about one in 10 skin cancers, can be fatal. More than 7,000 people in the UK are diagnosed with malignant melanoma each year.

Three years ago, Marais and his colleagues showed that the protein kinase called B-RAF is mutated in about 70 percent of human malignant melanomas. Their subsequent work showed that if they added mutant B-RAF protein to cultured mouse melanocytes in vitro, the cells would behave more like cancer cells.

Normally, melanocytes have a form known as dendritic: The cells have long processes similar to nerve cells. But when mutant B-RAF was added, they began to look more like immature melanocytes, taking on a form that is described as fibroblastic - in other words, they became much less differentiated.

Secondly, melanocytes to which mutant B-RAF had been added stopped making melanin. Again, that change meant that the cells were less differentiated.

Marais and his group set out to understand how the biological changes came about. They decided to investigate the role of MITF in melanocytes, because they knew from research carried out by other groups that mice lacking functional copies of the MITF gene had no melanocytes at all.

Their own studies demonstrated that when they added mutant B-RAF to melanocyte cell cultures, the melanocytes stopped expressing MITF.

Marais said, "These findings made us think that perhaps one of the key functions of B-RAF in melanoma was to turn off expression of MITF."

They were not sure whether loss of MITF expression was an inconsequential side effect of loss of normal B-RAF function, or whether the two molecules operated in the same biological pathway.

To determine the answer to that question, they carried out their latest study, funded by Cancer Research UK, which is reported in the Aug. 29, 2005, issue of Journal of Cell Biology in a paper titled "Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation."

Marais explained: "When we put mutant B-RAF into the melanocytes, they start growing uncontrollably, they lose expression of MITF, and they lose their identity and become like cancer cells. When we put MITF back into the cells they stop growing, even though they still contain mutant B-RAF. So we can conclude that lack of MITF has a very important biological consequence for these cells - it is a controller of growth, and it gives melanocytes their identity."

The paper described how, 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 about 70 to 80 percent.

Marais and his colleagues at the Institute of Cancer Research already are working on drugs that target mutant B-RAF. The latest discovery is important because it shows that the drug development work is on the right track, Marais said.

"It may also allow us to predict how individual patients' tumors might develop, or how different individuals will respond to different therapeutic agents or combinations of agents," Marais added. "It will also help us to develop new therapeutic agents, and gain a better understanding of how existing treatments work."

As well as identifying new drug targets, Marais and his colleagues now want to understand how B-RAF turns MITF on or off, and particularly whether B-RAF does that by modulating the gene encoding MITF, or the protein itself. He said, "We also want to know what are the biological consequences of removing MITF from cells - exactly how does this molecule regulate cell growth and differentiation?"

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