The January issue of Science reported that
researchers had successfully extended the lifespan of normal human
cells using the enzyme telomerase to lengthen telomeres. Reaction to
these initial findings was guarded. Oncologists were concerned that
the process could be cancerous. Now, new research presented at the
annual meeting of the American Association for Cancer Research (AACR)
demonstrated that these cells continue to divide and maintain normal
structure and function and do not progress toward cancer.
Calvin Harley, PhD, chief scientific director at Geron Corporation,
and Jerry W. Shay, PhD, professor of cell biology and neuroscience at
the University of Texas Southwestern Medical Center in Dallas,
authors of the initial study published in Science, reported that
telomerase-positive skin and retinal cells, as well as cells from
the vascular endothelium, doubled their lifespan, while maintaining a
normal chromosome count without signs of cancerous transformation. In
addition, they found that the telomerase-positive cells have shown no
signs of telomere loss, nor do they behave like senescent cells in
their pattern of gene expression.
"We have been able to dramatically extend the lifespan of normal
cells using telomerase beyond that which we reported in our initial
studies in January," said Dr. Harley. "There are novel and
promising therapeutic opportunities for this technology. In addition,
the causal links between telomerase, telomere length, and cell
lifespan provide further validation for telomerase inhibition as a
potentially safe and universal approach to anticancer therapy."
Telomerase Involved in Normal Blood and Sperm Production
In humans and mice, adult organ systems populated by undifferentiated
cycling stem cells express telomerase activity. In addition, abundant
telomerase activity is present in the vast majority of human cancers
and immortal cell lines. In another study presented at the meeting,
Ronald A. DePinho, MD, professor of microbiology and immunology and
of medicine at Albert Einstein College of Medicine and Carol W.
Greider,PhD, associate professor of molecular biology and genetics at
Johns Hopkins University School of Medicine and their colleagues
deleted the telomerase RNA gene in a mouse to determine the
possibility that telomerase plays a role in the maintenance of stem
cells and in the growth of immortal cancer cell. They then examined
hematopoietic and germ cells in successive generations of the
telomerase RNA gene-deficient mice.
They found that the mice exhibited defective spermatogenesis with
increased apoptosis and decreased proliferation in the testis. The
proliferative capacity of the hematopoietic cells in the bone marrow
and spleen was also compromised. These deleterious effects on the
hematopoietic and germ cells coincided with substantial telomere
erosion and chromosome fusions and loss.
"Together, these findings establish an essential role for
telomerase, and hence telomeres, in the maintenance of chromosomal
integrity and in the long-term viability of high-renewal organ
systems, such as the blood-cell and sperm-producing cells," said
Dr. DePinho. "With respect to cancer, telomerase-deficient cells
are still capable of spontaneous immortalization and tumor formation.
However, the rate of immortalization in cells cultured in the
laboratory and the rate of cancer formation observed in animal models
are significantly reduced. These studies indicate that, while
telomerase activation is not absolutely necessary for cellular
immortalization and transformation, telomerase-deficiency can impede
this important growth transition."
Telomerase Shows Promise for Cancer Diagnosis and Monitoring
Other research by Dr. Shay demonstrated the utility of telomerase in
early cancer detection and as a prognostic indicator of outcome.
"The diagnosis of cancer is almost always made by pathologists
who must rely primarily on their experience in identifying subtle
cellular alterations, making diagnostic pathology an inexact science.
Despite progress in the development of more accurate diagnostic
methods, most do not have sufficient specificity or sensitivity to
identify a variety of cancer types. Therefore, new tests, applicable
to most types of cancer, are needed," said Dr. Shay.
Studying esophageal tissue for telomerase RNA, Dr. Shay was able to
identify telomerase-positive cells in 100% of the carcinomas and in
90% of the low- and high-grade dysplasias. In Barretts
metaplasia, moderate levels of telomerase RNA were detected in 70% of
the specimens. "These findings could potentially help stratify
high-risk patients and provide prognostic value," said Dr. Shay.
In a study of pancreatic cancer, Dr. Shay and his colleagues used a
nonsurgical endoscopic procedure to determine whether pancreatic
strictures were due to the presence of pancreatic cancer cells. They
were able to correctly identify 62% of the malignant pancreatic
cancers by cytology alone, and 75% by telomerase alone.
"A definitive diagnosis of pancreatic cancer can be difficult,
and endoscopic pancreatic cytology historically has an overall
sensitivity of only 50%," said Dr. Shay. "However, using a
combination of both cytology and telomerase RNA detection, we were
able to identify all pancreatic cancers for an overall sensitivity of
100%. While this is only an initial study, the results strongly
suggest that a combination of diagnostic cytology and telomerase
molecular diagnosis may have important utility."
Furthermore, Dr. Shay found that testing for telomerase RNA in urine
samples from patients treated for bladder cancer following standard
surgery and adjuvant chemotherapy and radiotherapy is effective in
monitoring the patients progress. "Detecting recurrent
bladder cancer by testing for telomerase RNA, which is a noninvasive
procedure, may provide the same value as the more invasive and
uncomfortable cystoscopy. It may lead to better patient compliance
with follow-up procedures," he said. "In addition, this
test could eventually lead to a population-based screening method for
early cancer in high-risk individuals, such as smokers and those who
work in the chemical industry."