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DERMATOLOGY Sun May Cause Cancer By Targeting Rb PathwayFinding Could Lead to New Methods for Diagnosing Early Melanoma A team of Dana-Farber Cancer Institute researchers has made a discovery that could help solve a centuries-old mystery in cancer biology: how a sunburn acquired during a childhood day at the beach develops into a deadly melanoma decades later. Lynda Chin and her colleagues report in the Feb. 4 Proceedings of the National Academy of Sciences that the ultraviolet rays of the sun direct their cancer-causing darts to a specific molecular cascade inside the young skin cell, the Rb pathway, impairing its ability to regulate proliferation.
Like most cells, melanocytes regulate their growth by means of two pathways, p53 and Rb. Downstream signals in each pathway (purple shaded region) promote survival and proliferation. Upstream signals such as p19 and p16 put a brake on such growth activities. Ultraviolet radiation attacks the Rb pathway of melanocytes in at least two ways. It disables the growth-inhibiting p16, and it causes the growth-promoting cdk6 to be overexpressed. The result is unrestrained growth. (Image by Jeff Cleary) The researchers found that they could increase not just the number of tumors but also their speed of formation by exposing newborn mice to ultraviolet radiation, but the pups needed to have their Rb pathway intact. Named for the retinoblastoma (Rb) tumor suppressor protein, the pathway plays a key role in the cell cycle. Those mice in which the pathway was already essentially knocked out were unaffected by the dose of radiation. "It looks like the Rb pathway is specifically targeted by ultraviolet radiation," said Chin, HMS assistant professor of dermatology at DFCI. The findings are both timely and unexpected. Melanoma, the most pernicious form of skin cancer, is one of the fastest spreading cancers in the country, with the number of new cases more than doubling over the last three decades. The only completely effective treatment for these lesions, the majority of which are thought to be acquired early in life, is surgery--and only if caught in time. The discovery that ultraviolet radiation triggers melanoma by dismantling a specific pathway in the skin's pigment-producing cells offers the possibility of an efficient means of distinguishing, at an early stage, cancerous moles from those that are noncancerous.
"What we hope to do in this study is to identify areas of investigation that can be probed in humans," said Lynda Chin. (Photo by Steve Gilbert) "If you see in a sun-induced lesion that its Rb pathway has been inactivated, then the risk of it becoming a melanoma is much greater" than in one with an intact Rb pathway, said Chin. "You could then use that as a prognostic factor to determine which of these funny-looking moles needs to be cut out with a wide margin around it." Karrupiah Kannan and Norman Sharpless, formerly at DFCI, are first authors on the study. The UV EffectThough there were hints that the Rb pathway might be particularly susceptible to environmental attack, the discovery that it is specifically targeted by ultraviolet radiation is surprising for several reasons. To begin, UV was thought to be a less picky carcinogenic agent, targeting multiple pathways in the cell. "Traditionally, people think of UV mutation as a specific C to G mutation, the so-called UV signature," Chin said. Yet when the researchers explored the DNA in the tumors of the UV-affected mice, they found a more massive disruption. A whole region of chromosome 5 appeared to be amplified, suggesting that the radiation had actually caused the double-stranded DNA molecule to break.
Perhaps most significant, the findings suggest that Rb may be a kind of molecular dark horse in the human melanoma story. Human melanomas have long been known to exhibit defects in their Rb pathway, but they also exhibit mutations in their Ras and p53 pathways. All three kinds of mutation are needed for a tumor to emerge. Based on genetic studies in mice, many thought the p53 mutations were more important than the Rb mutations. Opinion began to shift more than a year ago, when Sharpless, then an HMS clinical instructor in medicine, and other DFCI researchers reported that mice engineered to lack a gene in the Rb pathway, p16, developed tumors at a faster rate when exposed to carcinogenic chemicals. Prompted by the findings, Sharpless and his colleagues suggested that the normal function of the Rb pathway might be to tell the cell to stop dividing in the presence of environmentally induced damage. To explore this hypothesis, and to compare more generally the role of the Rb and p53 pathways in melanoma, Kannan, Sharpless, Chin, and their colleagues exposed newborns of two strains of genetically engineered mice--one lacking p19, a critical component of the p53 pathway, and one lacking the Rb-pathway protein p16--to ultraviolet radiation. (Both strains carried the Ras mutation, making them especially cancer-prone.) The p19 mutants, whose Rb pathway was intact and therefore vulnerable to attack, had a higher chance of developing melanomas when exposed to UV radiation--85 percent compared to 50 percent in unexposed litters. They also developed more tumors, two to three compared with one in the nonexposed group. And the lesions appeared on average six weeks sooner. The p16 mutants, whose Rb pathway was already defective and therefore impervious to additional ultraviolet insult, 0exhibited no such difference. Their chance of developing tumors was the same whether or not they were exposed to ultraviolet radiation, even though their p53 pathway was theoretically susceptible to attack by UV. Likely TargetsPuzzled about where in the Rb pathway the ultraviolet agent was aiming, the researchers compared both the DNA and the gene-expression patterns of melanomas from the UV radiation-exposed p19 knockouts and the unexposed mice, who presumably developed their tumors spontaneously. While loss of p16 function showed up in the expression patterns of 50 percent of the unexposed mouse tumors, it appeared in only 20 percent of exposed mutants. "That suggested to us that in UV treatment, there is another way of hitting the Rb pathway," said Chin. On further examination, they found that another gene, cdk6, was overexpressed in the majority of the UV-induced tumors. Not only that, the gene, which sits on chromosome 5, appeared to be duplicated.Why this gene, which was not turned on in any of the spontaneously developing mouse tumors, should be especially vulnerable to ultraviolet perturbation is not clear. Nor is the cdk6 gene ultraviolet radiation's only likely target. Though it was overexpressed in the majority of the ultraviolet-exposed tumors, many lesions exhibited as-yet unknown defects. "The data suggest that UV is really targeting the Rb pathway rather than specific components," said Chin. Such a strategy would make sense if the Rb pathway were the cell's main environmental carcinogen sensor, she added. Turning the findings into a tool for diagnosing human melanomas will require more basic research. "People have not thought to correlate Rb status with sun exposure history and progression of pigmented lesions," Chin said. Further research could provide an answer to the conundrum of skin cancer's origin. Ultraviolet radiation, first identified as a carcinogen in 1850, is thought to do its greatest damage early in life. In fact, most melanomas appear to be traced to childhood sun exposures. What makes young melanocytes so susceptible to melanoma-producing damage? One possibility is that they are still in the process of differentiating and therefore less able to carry out their main physiological task of responding to ultraviolet radiation. "It is possible that early melanocytes are serving different functions and are more susceptible to ultraviolet radiation," said Chin. "Also, gene activation patterns change during development. As melanocytes mature, certain genes may endow the cell with the ability to resist UV." --Misia Landau |
