An international team of scientists reports that determining the telomerase level may help alleviate uncertainty in making decisions regarding breast cancer therapy, where treatment is disfiguring and controversy exists over the extent of treatment.
The researchers, from the University of Texas Southwestern Medical Center (Dallas) and the Hiroshima University School of Medicine in Japan, used a PCR-based assay on 140 breast cancer specimens sampled during surgery to remove tumors and also from 33 samples obtained with fine-needle aspiration, a common method used to sample tissue from a small breast lump or suspicious region detected with mammography. Samples of noncancerous breast growths served as controls.
Of the 140 breast cancers, 130 (93%) demonstrated telomerase activity. The more advanced the cancer, the more likely it was that telomerase would be found. "Weíve shown that of women with the earliest stage, 68 percent show telomerase activity. Among women with stage II or above, which means a larger tumor, 98 percent have telomerase activity," says Jerry Shay, Ph.D., professor of cell biology and neurosciences at the medical center in Dallas.
He is especially excited about the data on the fine-needle aspirates, which give surgeons an idea of the type and extent of disease. Of the 33 fine-needle aspirates, 15 had telomerase activity, and 14 of these were cytologically suspected to be malignant. Following surgery, all 14 cancers were found to be invasive. Of the 18 samples lacking telomerase activity, 17 were suspected to be benign. One was borderline and found after surgery to be invasive.
Dr. Shay envisions telomerase measurement as one day becoming part of the diagnostic work-up for breast cancer. "For an early-stage cancer, youíd do a needle biopsy, and if there is telomerase activity, the surgeon would know, prior to the surgery, that it will need more extensive margins plus adjuvant chemotherapy. If the early-stage sample shows no telomerase activity, the surgeon can perhaps do a lumpectomy and not do anything else," he says. Better tailoring extent of treatment to extent of disease could avoid overuse of treatments that can cause secondary cancers. The National Cancer Institute plans to hold a workshop in June on early detection of cancer using telomerase activity, Dr. Shay adds.
Clinical Outcome
In addition to being directly correlated to cancer stage, telomerase activity may also predict probable clinical outcome. Dr. Shay has led much of the recent work measuring telomerase activity in cancer cells and is overwhelmed by the current level of interest. "What started out as simply a new PCR assay to measure telomerase activity turned into the most novel molecular marker for cancer to come along in a while," he says.
Studies in ciliated protozoans have demonstrated that telomerase is active and the cells divide, producing more of the single-celled organisms. In a multicellular organism, however, unchecked cell division gives a proliferative advantage to some cells, yielding an abnormal growth. Therefore, normal somatic cells do not appreciably express telomerase, if at all. Instead, in cells like those of humans, telomeres erode slowly with each cell cycle, eventually reaching a point that somehow signals "stop" to the cell division clock. Telomere shortening seems to explain the Hayflick limit, the fact that somatic cells divide a certain number of times and then stop.
Because cancer cells are notorious for ignoring the Hayflick limit, researchers werenít surprised to discover that chromosomes in cancer cells do not shorten. The first evidence came in 1989, when Gregg Morin, Ph.D., and his team in the department of molecular biology at the University of California, Davis, detected telomerase activity in HeLa cells, which are immortal.
Five years later, Christopher Counter, Ph.D., Silvia Bacchetti, Ph.D., and Hal Hirte, Ph.D., at McMaster University in Hamilton, Ontario, plus Calvin Harley, Ph.D., formerly of McMaster but relocated to Geron Corp. (Menlo Park, CA), reported finding telomerase activity in ovarian cancer cells from patients. Later that year (l994), Dr. Shayís group, with collaborators at the Hiroshima University School of Medicine, reported telomerase activity in 90 of 101 biopsies from 12 types of human tumors, plus no activity in 50 samples of normal somatic tissue. The link has strengthened ever since.
Other Cancers
Like classic cytology that looks for telltale signs of a cell turned cancerous, assaying telomerase for diagnostic or prognostic purposes would apply to many types of cancer. Neuroblastoma, a childhood cancer, is one of them. Before the breast cancer finding, the Dallas and Hiroshima groups reported on telomerase activity in l00 children with neuroblastoma. Of the group, 94% had telomerase activity. Tumors with the highest telomerase levels tended to have genetic changes and poor clinical outcomes, whereas tumors with lower telomerase levels lacked genetic changes and often had a better outcome.
Acute myelogenous leukemia (AML) is another condition where telomerase level may have prognostic value.
"AML is a very aggressive disease. For those individuals whose tumors have high telomerase activity, one year later, 20 percent are alive. But for the 20 percent of patients who have low levels of telomerase, 40 percent are alive two years later. Therefore, telomerase activity may be a prognostic indicator," says Dr. Shay, who also foresees telomerase assays for bladder cancer performed on cells collected from urine and for colon cancer performed on cells collected from colonic washes.
Telomerase Kits
Researchers at Geron, who are currently working on developing inhibitors of telomerase to treat cancer, are obviously quite excited about the possible prognostic power of telomerase. "The data collected by Jerry Shay and others linking the level of telomerase expression with the stages of various cancers are very intriguing. These types of research observations suggest that a measurement of telomerase should be valuable as a diagnostic or prognostic tool," says Dr. Harley, vice president, research, and a pioneer in telomere research. He adds that the observations must be repeated for each type of cancer in controlled clinical trials.
"These studies are under way and, if successful, Geron will form appropriate partnerships to develop and commercialize kits to assist physicians in using this new tool for diagnostic or prognostic purposes," says Dr. Harley.
Dr. Shay estimates that a telomerase assay would cost between $100 and $200 and suggests it might be used one day to mass screen older people to detect various cancers at treatable stages. "In a couple of years, there will be enough studies for telomerase to be useful diagnostically in patient care," he predicts.
As for all the excitement over this most unusual enzyme, Dr. Shay adds, "the optimism is justified for now."
The Dallas and Hiroshima team published their study on telomerase and breast cancer in the January 17 issue of the Journal of the National Cancer Institute (Eiso Hiyama et al, JNCI 88:116-122, 1996).
By Ricki Lewis, Ph.D.
Ricki Lewis, Ph.D., is the author of several biology textbooks and writes from Scotia, NY.
feedback form |
permissions |
international |
locate your campus rep |
request a review copy
Copyright ©2001 The McGraw-Hill Companies.
digital solutions |
publish with us |
customer service |
mhhe home
Any use is subject to the
Terms of Use and Privacy Policy.
McGraw-Hill Higher Education is one of the many fine businesses of the
The McGraw-Hill Companies.