IGFBP7 protein may stop melanoma skin cancer

Howard Hughes Medical Institute (HHMI) researchers have uncovered a protein that stops the growth of melanoma, a cancer that develops from pigment-producing cells in the skin called melanocytes.

HHMI investigator Michael Green and colleagues at the University of Massachusetts Medical School reported their identification of the genetic underpinnings of a new way to thwart one of the deadliest forms of cancer in the February 8, 2008, issue of the journal Cell.

Green and his colleagues began by designing experiments that would help them determine what separates melanomas from ordinary moles at the genetic level. Moles, also known as nevi, and melanoma often result from the same genetic mutation, and the biological pathway that differentiates the two had been a mystery. The new study uncovers a relatively unknown protein that regulates the melanocyte’s “decision” to ward off cancer by either entering a programmed hibernation or committing suicide.

According to the American Cancer Society, 60,000 people in the United States developed melanoma in 2007, and more than 8,000 died of the disease. Melanoma is caused by the uncontrolled proliferation of melanocytes, whose pigment, melanin, protects the skin against the sun’s ultraviolet rays. Nevi, which are benign, are also caused by abnormal growth and differentiation of melanocytes.

While nevi are, by definition, non-cancerous, more than half the time the same mutation is at fault in melanoma and nevi: a single amino acid change in a protein called BRAF. BRAF is part of a signaling system that is important for cell growth and proliferation. The BRAF mutation found in nevi and melanoma increases the activity of the BRAF protein, prompting cells to multiply abnormally. In some melanocytes with this mutation, the proliferation cannot be stopped, and cancer develops.

But sometimes when the mutated BRAF gene is expressed in melanocytes, those cells go into a state of permanent hibernation via a process known as senescence. These cells form nevi, not melanoma. This, according to Green, indicates that the genetic checks and balances within those cells are working correctly. “The cell has sensed this oncogenic influence-activated BRAF-and that induces an anti-cancer mechanism to throw the cell into this frozen state,” he said. Green added that sometimes cells simply commit suicide instead of senescing.

Cancer results when something blocks this failsafe mechanism, said Green. “While this phenomenon was known, the components and the pathways involved were not,” he said.

Green, his postdoctoral fellow Narendra Wajapeyee, and their colleagues did a genome-wide search for the proteins involved. They used engineered retroviruses to insert short bits of RNA to selectively turn off individual genes in a series of melanocytes. Some of the cells progressed to cancer, while others did not. After testing thousands of genes, they found 17 that were required for activated BRAF to induce either senescence or suicide. Together, Green said, the proteins made by these genes make up the body’s melanoma defense pathway.

The team’s 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 IGFBP7’s ability to target melanoma tumors throughout the body may make it a powerful tool for cancer therapy. “We’re really very excited about the prospects of trying to advance this as a melanoma treatment,” he said.

Source: Howard Hughes Medical Institute, USA



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