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GENETICS Environmentally Induced Cancers Target Genetic Achilles HeelAs rescue workers comb through the smoldering ruins of the World Trade Center in New York, they face an insidious danger. The burning of the skyscrapers released asbestos and other cancer-causing chemicals with the power to seep through the face masks and makeshift filters that many workers are wearing.
The p16 gene, studied by Ned Sharpless, Ron DePinho (l to r), and their colleagues, appears to be targeted for modification by carcinogens. When p16 no longer functions, cancers develop more quickly. Photo by Steve Gilbert Although its long-term health effects remain to be seen, the recent tragedy brings new urgency to an old question: how do environmentally induced cancers arise? How do carcinogens—those encountered not just in disasters but in everyday life such as cigarette smoke and ultraviolet radiation—make their assault on cells, turning them into proliferating masses? A recent report by the Dana– Farber Cancer Institute's Ned Sharpless, Ron DePinho, and colleagues may hold important clues about how such cancers are formed—and how they may be fought. They have identified a gene that may be linked, in mice, to environmentally induced cancers. The gene, p16, seems to confer vulnerability in two ways. When defective or missing, it may hasten the progress of carcinogen-induced cancers. In fact, the researchers found that mice lacking p16 developed tumors twice as fast as controls after being exposed to cancer-causing agents. And the tumors were bigger and more aggressive, the researchers report in the Sept. 6 Nature. Even intact, p16 appears to be a genetic Achilles heel, one that is especially vulnerable to damage by cancer-causing agents. Sharpless, HMS clinical instructor in medicine, and his colleagues found that p16 was turned off in the tumors of even normal animals exposed to carcinogens. Upon closer examination, a molecular silencer was found attached to the majority of p16 genes, as though the genes had been specially targeted by the agent. "This raises the possibility that there is an intimate link between carcinogen-induced cancers and p16," said DePinho, HMS professor of genetics and medicine. A Protein for All CancersThe link between p16 and cancer appears to extend even further. In their experiments, the researchers found that mice lacking the p16 protein developed tumors much more frequently than controls even in the absence of carcinogens. This suggests that when present, p16 acts to suppress not just environmentally induced tumors but all kinds of cancers."It clearly establishes this gene product as a bona fide tumor suppressor that people need to pay attention to both with respect to diagnosis and with respect to potential therapeutic interventions," DePinho said. What makes the discovery especially interesting, he said, is that p16 happens to occupy the same patch of DNA as another tumor suppressor gene, p19. The two genes, p16 and p19, have overlapping DNA sequences. The difference between them is that they are turned on by different promoters, and the common sequence is translated differently because the codes are in alternate reading frames. Also, though both genes produce proteins that suppress tumor formation, they do so through different cellular pathways. P16 works by helping to brake cell proliferation, through the regulatory Rb pathway. P19 works through the p53 pathway to help cancer-prone cells commit suicide. "So a strategic hit could suppress the two most important tumor suppressor pathways," said DePinho. Indeed, the locus for the two genes is deleted not just in mouse cancers but also in a broad spectrum of human cancers. While the overlap of the two gene sequences helps to explain why their DNA makes such a good target for cancer, until recently it engendered a kind of rivalry between p16 and p19. For years, many thought that one of the two had to be more important. Indeed, a big question in cancer research was which one is the real tumor suppressor? In 1996, a group of scientists created a strain of mice lacking the p19 protein. The rodents looked very similar to animals lacking both p16 and p19, which led many to proclaim p19 the true tumor suppressor. Putting P16 to the TestTo settle the question, Sharpless and colleagues created a mouse lacking only the p16 gene product. Though the mice appeared normal, they exhibited telltale signs of cancer. To begin, their T cell–generating thymus was unusually large. Upon closer inspection, T cells appeared to grow faster. Compared to normal mice, the mutants were more likely to spontaneously develop tumors such as lymphomas and sarcomas.Sharpless and his colleagues knew that p16 loss in humans is associated with ultraviolet radiation–induced cancers (such as melanoma) and with cigarette smoke–induced cancers (such as tumors of the head and neck, lung, and bladder). So they exposed both the p16-deprived mice and controls to one of two carcinogens—DMBA or urethane. What impressed them was not just the way the loss of p16 seemed to increase the rate and size of cancer growth in the experimental mice, but also the way p16 appeared to be nonfunctional in the tumors of the normal animals. Wherever a defect could be detected in the unexpressed p16, it assumed the same characteristic form—the attachment of a methyl group to the p16 promoter. "It may be that p16 loss is a general feature of cancer, but our data suggest, though don't prove, that methylation may have something to do with the p16 loss found in environmentally induced tumors," DePinho said. If this is the case, it might be possible to rescue p16 in environmentally induced tumor cells by targeting the methyl group. "The gene is still there, it's just turned off," said DePinho. "With a methylation inhibitor—a small molecule—it may be possible to reactivate p16 in someone's tumor." In fact, the researchers added methylation inhibitors to mouse tumors and found that the methyl groups slipped off the p16 genes, and cancer growth halted. With regard to spontaneous tumors, which do not appear to be caused by methylation, the mouse findings also hold out therapeutic promise. "We can say that p16 is a very highly validated target," DePinho said. The fact that it plays such an important role in the mouse—which is evolutionarily closer to humans than many other experimental organisms such as the worm or Drosophila—makes it a prime candidate for targeting in preclinical trials. Does p16's newfound status as a tumor suppressor—and potential drug target—mean a demotion for p19? The answer appears to be—it depends. In the case of environmentally induced cancers, p16 loss is likely to be the more dramatic event. P19 loss probably looms larger in some spontaneous cancers. In other cancers, both may play a role. "So there's something special about p16 and there's something special about p19," DePinho said. "That's the bottom line result at this point." —Misia Landau |
