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 birth, as determined by terminal restriction fragment analysis, telomeres
Every time a cell divides, it loses 25 to 200 DNA base pairs off the
Telomerase, or telomere terminal transferase, is a ribonucleoprotein
Telomerase is present in most fetal tissues, normal adult male germ
After adding six bases, the enzyme is thought to pause while it repositions
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."