SAN DIEGO--Research involving telomerase, the protein thought to be responsible for cancer cell immortality, is experiencing explosive growth, and nowhere was that more evident than at the annual meeting of the American Association for Cancer Research (AACR).
At the conference, more than 150 symposiums, papers, and lectures were devoted to telomerase studies. In contrast, two years ago there were just four or five presentations at the poster sessions, while last year the number inched up to two dozen or so.
At next year's spring meeting, there very well could be up to 300 telomerase presentations, predicted Jerry W. Shay, PhD, professor of cell biology, University of Texas Southwestern Medical Center, Dallas. "This is one of the most exciting advances in cancer biology to emerge in the last decade," said Dr. Shay, who estimates that anywhere from 500 to 1,000 studies internationally are now focusing on telomerase activity.
Detailed Definitions of Telomere and Telomerase
Telomeres are repeated DNA sequences [(TTAGGG)n in humans] found at the ends of linear chromosomes that protect the ends of the chromosome from degradation. Telomeres may determine how many times an individual cell can divide.
At birth, as determined by terminal restriction fragment analysis, telomeres consist of about 15,000 base pairs of repeated TTAGGG DNA sequences, which become shorter with each cell division due to the end replication problem.
Every time a cell divides, it loses 25 to 200 DNA base pairs off the telomere ends. Once this pruning has occurred about 100 times, a cell undergoes senescence (or aging) and does not continue dividing.
Telomerase, or telomere terminal transferase, is a ribonucleoprotein enzyme (composed of both RNA and proteins) that uses its internal RNA component (complementary to the telomeric single stranded overhand) as a template in order to synthesize telomeric DNA (TTAGGG)n directly onto the ends of chromosomes.
Telomerase is present in most fetal tissues, normal adult male germ cells, inflammatory cells, proliferative cells of renewal tissues, and most tumor cells.
After adding six bases, the enzyme is thought to pause while it repositions (translocates) the template RNA for the synthesis of the next six base pair repeats. This extension of the 3´ DNA template end, in turn, permits additional replication of the 5´ end of the lagging strand, thus compensating for the end replication problem. Telomer-ase is often referred to as an immortalizing enzyme.
There is adequate support, he noted, for all the attention. His recent compilation of published studies through the end of 1996 found that telomerase activity was present in 85% (1,734/2,031) of primary human tumors and in less than 1% (1/196) of somatic tissue samples, except for proliferative cells of renewal tissues.
Dr. Shay said that telomerase activity has been detected in preinvasive lesions of such cancers as breast and lung in 30% (123/410) of cases. In other cancers such as pancreatic and colon cancer, it appears in 90% to 95% of early stage carcinomas, but not in preneoplasia. There are insufficient or conflicting data on ordinary meningiomas and on renal, ovary, prostate, and stomach cancers.
There is also evidence in neuroblastoma, acute myeloid leukemia, breast cancer, and gastrointestinal cancers that the presence of high levels of telomerase correlates with poor patient prognosis.
"There is a great deal of momentum among pharmaceutical companies to identify telomerase inhibitors," Dr. Shay said. At least a dozen companies are working to develop these drugs, and he estimates that clinical trials could start in four or five years, if not earlier.
Among the many scientists presenting findings on telomerase research was Eiso Hiyama, MD, of Hiroshima University School of Medicine, Japan, who has collaborated with Dr. Shay.
In his research, Dr. Hiyama attempted to measure whether telomerase activity could be used as a biomarker in pancreatic duct samples for the accurate diagnosis of early pancreatic cancer.
His lab detected telomerase activity in 95% of 43 pancreatic cancer specimens using the TRAP (telomeric repeat amplification protocol) assay, and did not detect such activity in any benign tumors.
Ex vivo pancreatic duct brushing was performed on the resected pancreatic tissues of 12 patients immediately after surgery. Telomerase activity was detected in all eight samples with pancreatic cancer but was undetectable in all four samples with benign disease, Dr. Hiyama said.
In 31 in vivo brushing samples obtained by endoscopy, 12 of 13 telomerase-positive samples were determined at surgery to be pancreatic cancer, and the remaining telomerase-positive case has been followed without surgery because cytologic exam found no malignancy.
On the other hand, all 18 telomerase-undetectable samples were cytologically negative, and of the six patients who have undergone surgery, all were shown to have benign disease. "These findings," Dr. Hiyama concluded, "suggest that telomerase activity in cells derived from pancreatic ducts may be a useful marker in the diagnosis of pancreatic cancer."