How Aggressive is
the Cancer? Study of
Lead to New Test
Alan Meeker and Elizabeth Platz: Telomeres, tiny regions at the ends of chromosomes,
get a bit shorter every time a cell divides. When they get too short, this can lead to cancer.
Telomeres are kind of like aglets, the little plastic tips on the ends of shoelaces; in fact, their name comes from the Greek words meaning “end” and “part.” They are tiny regions of repeated DNA sequences that cap the ends of chromosomes and help protect them from deteriorating. Just as an aglet doesn’t last forever — leaving you stuck with a shoelace that’s frayed on one end and hard to lace up — telomeres wear out, too, shortening a bit every time a cell divides.
Telomeres can also shrink because of oxidative damage, incremental wear-and-tear at the genetic level caused by diet and other environmental factors. When a telomere gets too short, the chromosome it’s supposed to safeguard — think of the poor shoelace — loses its stability, and this eventually can lead to cancer. “Cancer cells tend to have much shorter telomeres than normal cells from the same tissue,” notes telomere biologist Alan Meeker, Ph.D., The Virginia and Warren Schwerin Scholar. The most dangerous cancers — the ones that metastasize, or spread to distant sites — tend to be those with the most unstable chromosomes. This fact led Meeker, epidemiologist Elizabeth Platz, Sc.D., M.P.H., and pathologist Angelo De Marzo, M.D., Ph.D., along with colleagues at Harvard, to wonder whether the length of telomeres — in cancer cells, or even in normal cells that may be headed for cancer — may foretell how aggressive a man’s prostate cancer is likely to be.
“The clinical tools that we currently use to predict the risk of aggressive disease in men with clinically localized prostate cancer are imperfect,” De Marzo explains. “Inaccurate predictions make it harder for men and their doctors to determine the best course of treatment.” To address this problem, the scientists recently investigated the link between the length of telomeres and the risk of highly aggressive disease.
The team studied 623 men with clinically localized prostate cancer who underwent radical prostatectomy; the men were participants in a massive, long-term investigation called the Health Professionals Follow-up Study. Of these men, 48 died of prostate cancer. The team analyzed the tissue that was removed during surgery, and measured telomere length using a method developed by the Hopkins investigators, called TELIFISH, for telomere-specific fluorescence in situ hybridization. After calculating the typical length of the telomeres in these cells, and then looking at the variation in telomere length from cell to cell, the scientists then correlated the length and variability to the men’s risk of dying of their prostate cancer over the next 10 years after their surgery. They took into account each man’s pathologic stage and Gleason score, as well.
“We found that men with more variable telomere length in their prostate cancer cells had a three-times-higher risk of dying of their prostate cancer,” says Platz. “We also found that men with shorter telomeres in their nearby stromal cells (smooth muscle cells and fi broblasts, cells in the connective tissue) had a six-times-higher risk of dying.”
Telomeres can shrink because of
oxidative damage, incremental
wear-and-tear at the genetic
level caused by diet and other
environmental factors. Cancer
cells tend to have much shorter
telomeres than normal cells.
The most aggressive cancers
tend to be those with the most
unstable chromosomes. Could
telomere length help predict these
Next, the investigators combined these two ways of looking at telomeres and found that men who had more variable telomere length in prostate cancer cells, and shorter telomeres in their stromal cells were 41 times more likely to die of their prostate cancer. “Equally importantly, we found that men who did not have this combination rarely died of their prostate cancer over the 10 years.”
These results are so promising that the team believes there is strong potential for a new clinical test to predict the aggressiveness of prostate cancer. The next steps are to streamline the process for determining telomere length, to test these fi ndings in other men with prostate cancer, “and to determine the optimal cutpoints for variability and short telomere length,” says Platz, “so that we can make this test as helpful as possible.”