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Genome-wide survey nets key melanoma gene
Date:2/7/2008

urely intracellular.

Green and his colleagues focused their attention on IGFBP7 because its presence suggested something intriguing: If one otherwise healthy melanocyte begins expressing BRAF, the IGFBP7 it produces can enter cells around it, prompting lots of melanocytes to switch off, rather than risking a tumor.

In the experiments reported in Cell, the researchers exposed human melanoma cells in culture to recombinant IGFBP7. The protein had the same genetic code as the human version, but was produced using genetically modified insect cells. The melanoma cells that were treated with IGFBP7 committed suicide-- just as though their anti-cancer mechanism was working correctly.

The researchers also injected the protein into the bloodstream of mice on to which human melanoma tumors had been grafted. IGFBP7 entered the tumor cells and stopped their growth in the mice. Melanoma cells [caused by BRAF mutations] shut off expression of this key regulator, said Green. Because of that, the cells escape from senescence and form a tumor.

According to Green, the research also answers another controversy in the field: Are nevi dead-ends or are they precursors to melanoma" If you go in and see a dermatologist, if they see a mole, they will generally cut it off, he said. They dont want to take the chance that it could be a precursor.

However, Green thinks his results point in the other direction. Because IGFBP7 is a secreted protein, even if one activated BRAF-containing -- but otherwise healthy -- cell in the nevi stopped producing IGFBP7 and threatened to form a tumor, the IGFBP7 being secreted from the cells around it would kill it. Its an extremely powerful anti-cancer mechanism, said Green.

The teams findings are important not only from a research standpoint, but also for future clinical treatments, Green noted. Melanoma can be surgically removed if caught early, but in advanced cases there is really no treatment for it. Green said IGFBP7s ability to
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
Source:Eurekalert

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