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."