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Full Text: COPYRIGHT 1995 American Medical Association WHAT MAKES cancer cells so deadly is their immortality. Normal somatic cells have a mitotic clock that keeps track of the number of times they divide. When that clock runs down, the cell ceases to replicate and becomes senescent. Most cancer cells, however, have found a way to stop their clocks. According to research findings reported at the American Cancer Society's 37th Science Writers Seminar, in New Orleans, La, the means to stop the mitotic clock appears to be an enzyme that is expressed in early fetal development by germline cells and most cancers, but not by normal somatic cells. The enzyme, called telomerase, enables the cell to maintain the integrity of its chromosomes each time it divides. Without it, the ends of the chromosomes, called telomeres, are whittled away until too much is lost for the cell to maintain normal function. At that point, it ceases to replicate. Telomerase is vital to maintaining the genetic integrity of germ cells and of somatic cells during the explosive growth of early fetal development. However, the gene or genes that express the enzyme appear to be turned off sometime before or shortly after birth, says Jerry W. Shay, Phd, professor of cell biology and neuroscience, University of Texas Southwestern Medical Center at Dallas. In most of the cancer cells he and colleagues have tested, the gene appears to have been switched back on. By stabilizing their chromosomes with telomerase, tumor cells are able to avoid senescence and divide endlessly, he says. "Telomeres are repeated DNA sequences found at the ends of chromosomes," Shay says. "Telomeres can be pictured as the plastic ends of shoelaces that are designed to protect and maintain the integrity of the shoelace." Each time normal somatic cells divide, they lose a piece from the ends of their telomere caps. At birth, the telomeres of human cells consist of approximately 15 000 base pairs of repeated TTAGGG DNA sequences. Every time a cell divides, it loses 50 to 200 DNA base pairs from each telomere. "When this pruning occurs about 100 times, a cell senesces," Shay explains. "When enough senescent cells accumulate over a normal life span, the individual may develop diseases associated with old age." The mechanism of DNA replication in human chromosomes is different for each of the two strands, called the leading and lagging strands. On the lagging strand, a gap occurs at the very end that cannot be filled in by enzymes that replicate the remainder of the DNA. Therefore, the telomeres become shorter after each cell division. Telomerase is a ribonucleoprotein that stabilizes telomeres by adding TTAGGG repeats to the ends of chromosomes. "Telomerase contains an RNA that it uses as a template to synthesize TTAGGG repeats directly onto telomere ends," Shay says. "This extension of the 3'-end, in turn, permits additional replication of the 5'-end of the lagging strand, thus compensating for the telomere shortening that would occur in its absence." Shay speculates that it may be possible to slow down the rate of telomere shortening and therefore slow the aging process. Because the most prevalent cancers are associated with age, slowing the rate of telomere shortening also may reduce the risk of cancer. In vitro experiments using human cell cultures are under way to test this theory. Secret of Cancer's immortality According to Shay, the presence of telomerase in cancer cells prevents telomere shortening and allows the cells to divide indefinitely. "We have detected telomerase activity in approximately 85% of primary human tumors examined," he says. "It may be possible to develop a simple therapy that inhibits telomerase activity and interferes with the growth of many types of cancer." Toward that end, Shay and colleagues are studying agents that may inhibit telomerase activity and force the cancer cells into a normal pattern of senescence and death. "We believe the treatment would be very selective in that only cells with activated telomerase would be affected. As far as we know, that includes only `immortal' tumor cells and germline cells. Our recent neuroblastoma studies indicate that tumors without telomerase activity do not continue growing and indeed eventually die." It is becoming clear that some tumor suppressors are not just cell cycle regulators, but key molecules essential for the induction of cellular senescence. "Alteration or mutation of p53 and the retinoblastoma gene, or possibly other oncogenes or tumor suppressor genes, may be sufficient to result occasionally in the development of cancer," Shay says, "but these would be predicted to be `mortal' tumors. The switching on of the telomerase gene, however, may be a critical event in the immortalization of tumor cells." Levels Vary With Tumor Grade Using a highly sensitive assay to measure telomerase activity, Shay and colleagues found no activity in any of 22 normal somatic cell cultures from 18 different tissues or in 50 samples of postmortem somatic tissues tested. However, they found activity expressed in 98 of 100 human immortalized cell lines and in 90 of 101 tumor biopsy specimens (Science. 1994;266:2011-2015). In another study, he and colleagues detected telomerase activity in 94 of 100 childhood neuroblastoma cases (Nat Med. 1995;1: 249-255). In addition, they found that telomerase activity was expressed at different levels depending on the tumor grade. In low-grade tumors (1 and 2), the enzyme was expressed at very low levels and the children had favorable outcomes following surgery and chemotherapy. However, in higher-grade tumors (3 and 4), telomerase was expressed at very high levels and the children had a much poorer prognosis. According to Shay, there is also a special subclass of advanced neuroblastoma called 4s, in which there are distal metastases but often spontaneous remission, even without surgery or chemotherapy. "A straightforward molecular explanation for cancer remission in these patients has been a mystery," he says. "In our study, we could not detect telomerase activity in three cases [in the series of 100 childhood cancers] of 4s neuroblastonia. It appears that because these tumor cells do not express telomerase activity, they eventually develop critically shortened telomeres and regress." These results suggest that there may be two pathways leading to the development of neuroblastoma, he says. One pathway may involve the failure to completely repress telomerase activity during fetal development and be associated with a good prognosis. The second may be associated with genetic changes, the subsequent reactivation and high expression of telomerase, and, in general, a poor prognosis. Spontaneous Immortalization Seen Spontaneous immortalization of human cells is an extremely rare event. Recently, Shay and colleagues reported the first documented case of spontaneous immortalization of "normal" human breast epithelial cells in culture (Mot Cell Biol. 1995;15:425-432). The cells were from a patient with Li-Fraumeni syndrome, a genetic disorder that involves germline mutations in the p53 gene. People with this disorder are at high risk of developing a variety of cancers, including early-onset breast cancer. According to Shay, "These findings suggest that continued proliferation of most tumor cells is dependent upon the activation of telomerase. Therefore, development of anticancer agents based on telomerase inhibition may be highly effective." Because normal somatic cells do not express telomerase, such agents are likely to have high specificity with low toxicity and few adverse effects. The efficacy of such agents, however, would be delayed. Treated tumor cells would stop proliferating only after passing a number of divisions related to their telomere length at the time of treatment. "A likely scenario would be to use conventional therapies to remove most tumor cells and then use antitelomerase treatments to prevent the extensive proliferation needed for regrowth of the tumor or micrometastases," according to Shay. In addition, testing for telomerase activity may provide clinicians with a useful diagnostic and prognostic tool. In their initial studies, the researchers found telomerase activity in nearly all axillary lymph node-positive breast tumors, but in only 25% of lymph node-negative breast tumors. "The presence of telomerase activity in node-negative tumors could potentially indicate a higher probability of cancer recurrence," Shay says. "In the future, this finding could possibly influence conventional surgical and chemotherapeutic decisions. Retrospective and prospective studies testing this hypothesis are in progress." The ability to detect telomerase in a few cancer cells may allow the detection of cancers at an earlier stage. In preliminary studies examining lung cells obtained by bronchial alveolar lavage in patients suspected of having cancer, the investigators were able to detect telomerase activity. Closing In On the Gene "We have observed that combining a telomerase-positive tumor cell with a normal cell into a single cell hybrid results in repression of telomerase," Shay says. "This indicates that there are normal gene products that suppress telomerase activity." He and colleagues were then able to show that they could halt telomerase activity by adding a normal chromosome 3 to the immortal tumor cell. Specific deletions on the short arm of chromosome 3 have been implicated in a number of human cancers, such as renal and small cell lung carcinoma and breast cancer. They are now seeking to clone the gene or genes responsible for telomerase control. In collaboration with Geron Corporation, Menlo Park, Calif, Shay is testing several potential therapeutic agents. He hopes to begin clinical trials in 2 to 5 years. "In unpublished studies, we have observed that 100% of basal cell carcinomas of the skin are telomerase positive," he says. "While most of these tumors do not become metastatic, many of them recur even after careful surgical excision. An early clinical trial may seek to determine if recurrence of such tumors is reduced if a telomerase inhibitor is included in the treatment protocol. Other early clinical trials will likely be in patients with metastatic cancer, such as small cell lung cancer or breast cancer, in which other treatment modalities have failed."Thank you for visiting my page at Angelfire. Please come back and visit again!
