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Cancer 'Clocks' May Be Therapy Target
By Adam Marcus, HealthDayNews
November 18, 2003
Can tumors tell time?
Yes, evidently. Tumor growth and response to treatment appear to depend heavily on "clock" genes. Scrambling those timing systems could help scientists treat malignancies, researchers report.
In a new study, scientists have found tumor growth is highly dependent on time of day, and that the timing of the gene activity in tumor cells is at least partly off kilter. In another study, researchers found mice missing a key gene that regulates circadian rhythm -- biological cycles that follow the solar day -- become highly prone to cancer. Results of each study were presented Nov. 18 at a meeting of the International Conference on Molecular Targets and Cancer Therapeutics in Boston.
Scientists have identified at least eight genes that regulate circadian timing at the cellular level. These genes govern everything from when cells multiply to when they decide it's time to self-destruct, framed by a roughly 24-hour day.
There's evidence that circadian rhythm has a role in cancer. Tumor cells are more vulnerable to anticancer drugs at certain points in their circadian cycle. Doctors already exploit this fact with ovarian cancer, for example, and studies show that properly timing drug treatment can quadruple the five-year odds of survival. The same strategy applied to childhood leukemia can increase a patient's odds of living five years after diagnosis by as much as 40 percent.
In addition, shift workers, whose circadian cycles are addled by their odd hours, appear more prone to certain cancers.
"There are good clinical reasons to think that cancers listen to time," says Dr. William Hrushesky, one of the pioneers of the search for tumor timing mechanisms. Hrushesky, director of research at the WJB Dorn VA Medical Center in Columbia, S.C., helped conduct one of the two studies presented at the cancer meeting.
If one engine of cancer is altered timing genes, correcting those errors could set tumor cells straight, he says.
Looking at mice with breast cancer, Hrushesky's group showed that sick animals had normal circadian rhythm based on standard measures, such as wheel running and sleep-wake cycles. They also found that the animals' tumor cells grow faster during periods of activity than in down times.
They then compared the activity of three circadian genes in tumor cells and those in normal liver tissue. One of the genes showed similar activity, but two were quiet in the cancerous cells.
"Tumors do keep circadian time, but not totally normally," says Dr. Patricia Wood, a cancer researcher at the Dorn VA. "If in some way you disturb the clock, you disturb tumor growth. If you make the clock abnormal, you make [the tumor] grow faster."
In the second study, researchers at Baylor College of Medicine in Houston showed clock genes can serve as tumor-suppressing genes -- and when they're disrupted, cancer can sprout. Loning Fu, who led the study, and her colleagues looked at the effect on mice of mutations in a key circadian gene, called Period 2 (Per2).
They saw that cells with defective Per2 ignored DNA damage that would normally cause them to commit suicide. In other words, Fu says, "the cell has more potential to become cancer."
Fu says circadian gene mutations could help explain why some tumors become resistant to drugs that should kill them.
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