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Fundamental Finding Yields Insight into Stem Cells, Cancer; Opens Door to Drug Discovery

Few things about growing older are as inevitable and obvious as “going gray,?yet scientists have been unable to explain the precise cause of this usually unwelcome transformation. In a report posted today on the Web site of the journal Science, researchers from Dana-Farber Cancer Institute and Children’s Hospital Boston say they have found the cellular cause of graying hair while investigating the origins of malignant melanoma, the potentially deadly skin cancer.

The scientists traced the loss of hair color to the gradual dying off of adult stem cells that form a reservoir that spawns a continuous supply of new pigment-manufacturing cells, called melanocytes, that give hair its youthful hues. Not only do the non-specialized stem cells become depleted, they also progressively make errors, turning into fully committed pigment cells in the wrong place within the hair follicle, where they are useless for coloring hair. The new findings won’t lead to a scientific alternative to hair dyes any time soon, if ever, even if they do solve a longstanding puzzle about the underlying mechanism of graying. Of more interest to the researchers is the pattern of cellular signals that triggers the death of pigment stem cells, since melanoma is dangerous for the opposite reason –melanocytes proliferate uncontrollably to form tumors and are hard to kill with treatment. “Preventing the graying of hair is not our goal,?emphasizes David E. Fisher, MD, PhD, director of the Dana-Farber Program in Melanoma, and senior author of the Science paper. “Our goal is to prevent or treat melanoma, and to the extent this research is revealing the life cycles of melanocytes, which are the cells that become cancerous in melanoma, we would love to identify a signal that would make a melanoma cell stop growing.?Fisher and the report’s lead author, Emi K. Nishimura, MD, PhD, also of the melanoma program, are in the Department of Pediatric Oncology at Children’s Hospital Boston as well as at Dana-Farb er. The second author, Scott R. Granter, MD, is a pathologist at Brigham and Women’s Hospital. The American Cancer Society expects about 55,100 people to be diagnosed with melanoma, the most serious form of skin cancer, in 2004, with an estimated 7,910 deaths. Melanoma can be cured when it is detected and treated early, but if the lesion penetrates deeply into the skin it is often fatal. Sun exposure is a major risk factor in the disease, which has been increasing in the past several decades. Melanocytes, which manufacture and store the pigment that combines with hair-making cells called keratinocytes to color the hair, are specialized cells spawned by colorless melanocyte stem cells. These cells were discovered by Nishimura in 2002. A pool of undifferentiated melanocyte stem cells resides in the hair follicle, and during the hair’s grow-and-rest cycle, the stem cells give rise to color-making melanocytes that journey to the bottom of the hair follicle: That is where they tint the keratinocytes with the person’s characteristic hue. By studying mice at progressively older intervals, Fisher and his colleagues discovered that as the rodents aged and their hair began turning gray, the numbers of stem cells diminished in proportion to the loss of color. The scientists were surprised to observe that, at the same time and the same rate, differentiated, pigmented melanocytes were showing up in the follicle at the location where the stem cells resided. Since they were in the wrong place, the pigmented cells likely did nothing to maintain the mice’s hair color. To see if the cells behaved the same way in humans, the investigators examined human scalp tissue taken at increasing ages, and determined that the same pattern occurred. Since cell survival in general is influenced by an “anti-death?gene called Bcl2, Fisher’s team analyzed mice lacking this gene. In a dramatic fashion, the mice lost their melanocyte stem cells shortly after birth and quickly went gray. It may be that people who gray prematurely have mutations that knock out Bcl2 activity, Fisher says. “This tells us there is a requirement for Bcl2 in normal hair follicle cycling,?adds Fisher. “So the question is: what in the hair follicle is signaling the stem cells that is absent when aging occurs and the stem cells die off? Now we have a much more refined way of dissecting that signaling pathway in melanoma. Eventually we hope to tap into this death pathway, thereby using drugs to mimic the aging process, to successfully treat melanoma.?The team also made mice lacking a gene, MITF that regulates Bcl2. These mice also went gray, but more gradually than did the mice that had no Bcl2. The loss of MITF activity, the investigators say, appears to be implicated in the mistaken differentiation of melanocyte stem cells that accompanies the stem cells?depletion. MITF, they conclude, seems to play a crucial role in maintaining the supply of stem cells within the hair follicle, and graying is the result of “incomplete maintenance of melanocyte stem cells.?The research was supported by the National Institutes of Health, and Nishimura received funding from The Shiseido Award in 2002 and The Charles A. King Trust of Fleet National Bank and The Medical Foundation.


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