The link between aging and cancer is now clearer thanks to a new study that connects a powerful cancer-causing protein to a gene associated with Werner syndrome, a disease that causes premature aging.
Carla Grandori, M.D., Ph.D., of Fred Hutchinson Cancer Research Center, and colleagues report in the July issue of Genes & Development that the cancer-promoting activity of Myc - a protein implicated in breast, prostate and many other tumors - depends in part on its ability to activate the WRN gene, whose absence leads to Werner's syndrome.
Based on their results, Grandori and co-investigators at Fred Hutchinson, the University of Washington School of Medicine and Columbia University speculate that a novel class of anti-cancer therapies might be developed based on drugs that interfere with the anti-aging properties of the WRN gene.
Werner syndrome is a rare genetic disorder that develops when the WRN gene is missing or defective. The disease causes the onset of premature aging shortly after puberty and results in the appearance of old age when patients are 30 to 40 years of age. The syndrome is thought to occur because mutations in WRN cause genetic instability, a condition in which chromosomes are dramatically rearranged. Because genetic instability is also a common feature of tumor cells, Werner patients often die prematurely of cancers.
But the cancers that result from loss of the WRN gene differ from the tumors that are triggered by Myc, which require an intact WRN gene, said Grandori, a staff scientist in Fred Hutchinson's Human Biology Division and lead author of the paper.
"No one had implicated the Werner syndrome gene as a general pro-tumor agent," she said. "Patients with Werner do develop cancers, but they are very rare cancers and tend to occur later in a patient's life. They don't develop Myc-related cancers, and our findings help to explain why."
Myc already had been known to cause cell immortality, a characteristic that enables tumors to grow indefinitely. Grandori and colleagues in Riccardo Dalla-Favera's laboratory at Columbia University discovered in 1999 that Myc switches on telomerase, an enzyme that extends the lifespan of cells.
"Although telomerase is important for immortalizing cells, it's not sufficient in all cell types," she said. "We asked, 'What other gene could be important for preventing senescence?' The Werner syndrome gene was an obvious candidate."
Using human cells grown in the laboratory, Grandori found that when Myc was overproduced, activity of the Werner syndrome gene was similarly induced and cells became immortalized.
In cells in which the Werner syndrome gene was missing, an overabundance of Myc caused the cells to rapidly age. Aging cells have a flat appearance, stop dividing and have a unique pattern of gene expression.
Grandori said the these results suggest that it may be possible to block Myc's tumor-promoting activity by inhibiting the WRN gene, which would cause the cells to begin the aging process and cease to grow. She speculates that such drugs would be unlikely to mimic the symptoms of Werner syndrome.
"If cancer cells have higher levels of WRN than normal cells, tumor cells are likely to be more susceptible than healthy cells to drugs that inhibit WRN, so that normal cells would be relatively unaffected by the treatment." she said. "This could be a new approach for treating many cancers, since Myc is associated with numerous tumor types."
This research was funded by grants from the National Institutes of Health and the Nippon Boehringer-Ingelheim Virtual Research Institute on Aging.
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 39 nationwide. For more information, visit the center's Web site at http://www.fhcrc.org.
Journal
Genes & Development