Sci. Aging Knowl. Environ., 28 June 2006
The Age of Cancer
Cancer cells quiet gene behind premature aging disorder
The biggest risk factor for cancer isn't smoking or bad diet or anything a person can avoid. It's growing old. New findings might help explain the connection between aging and cancer. According to the study, a gene that's faulty in a disorder that resembles accelerated aging shuts down in many cancers.
Researchers have identified several possible reasons why cancer picks on the elderly, including the amount of time needed to amass the necessary mutations (see "Dangerous Liaisons"). One source of clues about the link between cancer and aging is Werner syndrome. When patients with this disorder hit their teens, life seems to speed up. Their hair turns gray, their skin wrinkles, and they develop cataracts, osteoporosis, and other hallmarks of old age (see "Of Hyperaging and Methuselah Genes"). But researchers are still debating whether Werner syndrome is in fact accelerated aging. The disorder stems from defects in the WRN gene, whose protein unravels the DNA double helix and chops out nucleotide bases, prerequisites for repairing a damaged strand (see Cheng and Bohr Perspective and Fry Review). Cells with faulty WRN incur chromosome damage that can trigger cancer, which kills many Werner patients before age 50. Researchers haven't found any tumors from non-Werner patients that carry WRN mutations, suggesting that the gene's sequence doesn't typically change in cancer. However, cancer biologist Manel Esteller of the Spanish National Cancer Centre in Madrid and colleagues suspected that tumor cells might be shutting down the gene's activity.
One way that cells muffle a gene is by tacking methyl groups to its promoter, or on-off switch. WRN's promoter sported the methyl decorations in four of the seven cancer cell lines the team tested, whereas normal cells were methyl-free. However, the cell lines came from three types of cancer--leukemia, colon, and breast--that rarely afflict Werner patients. But when the researchers subsequently checked 11 types of human cancers, they detected the methyl adornments in up to 38% of the growths, including types found in people with Werner syndrome, such as stomach and thyroid tumors. That finding suggests a common mechanism underlying cancer in Werner patients and other people.
To demonstrate that stifling WRN spurs cancer growth, the researchers inserted a pristine version of the gene into some tumor cells and left others with their methyl decorations intact. Compared with unaltered cells, cells that received a "clean" WRN grew more slowly in culture and spawned smaller tumors when injected into cancer-prone mice that lack an immune system. Overall, the work suggests that some cancer cells mothball WRN and "grow happily" without it, says Esteller. The findings also help clarify how aging increases cancer risk, he says. Esteller argues that DNA breaks promote aging, and that WRN combats aging by guarding the DNA. Shutting down the WRN gene not only accelerates bodily deterioration but also permits cancer to take hold, he says. The results suggest that newly developed antileukemia drugs that dislodge methyl groups might work against a variety of cancers, he says. Werner patients develop cancers that are rare in the general population. Why different tumors sprout in the two groups of people is unclear, says Esteller.
The study is important because it reveals an unexpected role for WRN in cancer that might help doctors target particular tumors, says molecular biologist Sherman Weissman of Yale University. The data are solid, adds cancer biologist Carla Grandori of the Fred Hutchinson Cancer Research Center in Seattle, Washington. However, she notes, the findings clash with previous studies that suggest losing WRN is disastrous for cancer cells; they accumulate lethal amounts of DNA damage. The next step, she says, is to determine how cancer cells prosper even with WRN shut down. Solving that question might help researchers learn how to keep the golden years from also being the tumor years.
June 28, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150