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Both inactivation of the p53 tumor suppressor pathway and activation of the serine/threonine kinase BRAF pathway are required for a mole to progress to melanoma, according to a study published recently in Current Biology. These findings suggest several points for therapeutic intervention to stop melanoma in its tracks.
First fish model Perhaps even more intriguing is that they are the first major cancer discoveries made using the zebrafish model. That animal system promises to become a significant adjunct to the mouse model, a mainstay of cancer research for decades, in understanding genetic and environmental factors in the development of cancers, and in screening potential therapies.
"About 90 percent of human moles have a mutation in the BRAF gene," says Leonard Zon, M.D., a Howard Hughes Medical Institute researcher at Children's Hospital Boston, who led the study.
Anything but simple The process began about five years ago when a post-doctoral candidate suggested to Dr. Zon, an expert in zebrafish, that the fish might make a good cancer model.
He says, "My mother died of cancer and I thought, if I could ever use the zebrafish as a model for cancer, I would."
The first step was to screen for mutants that affect the cell cycle. Establishing that baseline meant doing pathologies on about 20,000 fish.
"We sectioned the fish into five different planes and then evaluated with our pathologist whether the fish had cancer or not," he says. "That cost a huge amount of time and money, but it was worth it."
Still, when it came time for the next round of research, he sought a less expensive route and focused on melanoma "because it is so easy to see."
There are more than 200 mutant strains of zebrafish that have pigment problems, skin problems. Unlike the mouse melanoma, most zebrafish melanoma is pigmented, "and so perhaps this model is more closely related to humans," Dr. Zon suggests.
"We've created stable fish lines where every melanoblast, the precursor to the melanocyte, has activated BRAF. And we get moles occurring in those fish. When we mate them together with fish carrying the p53 mutant, we get melanomas."
Dr. Zon says, "The zebrafish's greatest attribute is that it's a genetic system. Each mother has about 200 babies every week, so it is a wonderful system if you are interested in trying to find genes that participate in skin cancer and melanoma.
"We actually found some new genes that are causing cancer in the zebrafish; now we are looking to see how they relate to human genes."
He takes pride in having already used the model to discover a genetic mutation that affects iron transportation.