A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions

An Enzyme that Holds the Key to Immortality

Hopkins Researchers, searching for an Achilles heel -- for any tiny chink in prostate cancer's impressive armor -- believe they've found a promising candidate in a fascinating enzyme called telomerase.

Donald S. Coffey, Ph.D., Director of Research

Prostate cancer is a fearsome foe, whose worst cells are, for all practical purposes, immortal -- utlimately impervious to treatment, once cancer has spread to the lymph nodes or bone.

But Hopkins researchers, searching for an Achilles heel -- for any tiny chink in prostate cancer's impressive armor -- believe they've found a promising candidate in a fascinating enzyme called telomerase. One day, understanding what this enzyme does may unlock riddles far beyond the prostate -- perhaps even expanding our grasp of how the body ages, and why it does.

And one day, cracking its mysteries may enable scientists to turn prostate cancer into vulnerable -- and killable -- mortals again.

"Every cell in the human body ages, and after a specific number of divisions, dies," says Donald S. Coffey, Ph.D., director of research. "Only the cancer cell has broken through this aging barrier. This means that these cells are capable of dividing on, and sustaining themselves, forever."

Think of a normal cell as a candle with a wick; in this case, the wick is a long strand of DNA. With every cell division, this wick shrinks a little; it loses a small piece of DNA. When this wick becomes too short, the cell dies. "This provides the counting mechanism for the biological clock," Coffey explains.

But in cancer cells, the wick doesn't get any shorter -- because of telomerase: This enzyme keeps replacing the DNA at the end of the strand, so there's not countdown. Like Dorian Gray, the cell never ages.

Coffey and colleagues have shown that telomerase is active in human prostate cancer cells, making them immortal. But it's notswitched on in BPH (benign prostatic hyperplasia), and in normal prostate cells.

Say you have a manuscript, says Coffey, "and on the front and back of the manuscript, you have 50 white, blank pages." The blank pages are filler -- meaningless, repetitive chunks of DNA that act as cushions for the really important part, the fragile genes inside. "Each time you go into the xerox room, you lose one of these pages. Every time you make a copy of the manuscript -- in other words, a new cell -- you lose a page. After you lose it down to a certain length, the cell becomes unstable and dies, and that's aging.

"Now, in cancer, somebody stands at the door of that room, and each time you go in, adds a new sheet onto the front and back." So for every sheet lost, one is gained, and the cell remains stable. "The white, blank pages are telomeres, the repetitive DNA at the end of each chromosome, and that person standing at the door is telomerase."

Coffey and colleague Alan Meeker are using a highly sensitive assay that can detect telomerase in as few as 10 cells, and works in needle biopsies of the prostate. Why is this important? Because currently, needle biopsies -- although much improved in recent years -- don't always give definitive answers. Sometimes the needle misses the cancer; sometimes what's under the microscope is almost impossible to label definitely as cancer. And even if cancer is seen in a few cells, is it the "good kind," so-called "incidental" cancer that, in millions of men, doesn't do much, but just sits in the prostate for decades? (In other words, could a telomerase test help determine if a man can afford to wait on treatment?) Or is the "bad" kind, cancer that needs to be treated as soon as possible? One days, Coffey speculates, a telomerase assay may mark cells that are not only cancerous, but "on the march" -- and potentially headed out of the prostate. Such a test may take much of the confusion out of many treatment decisions.

Even more exciting: If somehow telomerase could be blocked -- so cancer cells age and die like other cells -- then this might even be a way to make even advanced cancer curable one day. Says Coffey: "This could be an important target for future therapy."

Further Reading
"Telomerase Activity, a Prevalent Marker of Malignant Human Prostate Cancer," Cancer Research, Vol. 56, p. 218, 1996. H.J. Sommerfeld, Alan Meeker, Donald S. Coffey, et al.



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