Is Telomerase a Universal Cancer Target? (1995)

Perhaps one naive goal of cancer research is the discovery of a cellular component absolutely required for growth of all cancers but not for normal cells. This factor would be a universal target for therapeutic intervention. Could this elusive agent be the enzyme telomerase? Recent reports indicate that telomerase is expressed in more than 85% of all cancers but not in normal tissues (1-3). This editorial examines issues associated with using telomerase and telomeres in cancer therapy. Also in this issue of the Journal, Rhyu (4) more extensively reviews what is known about the roles of telomeres and telomerase in cancer. The inability of the DNA replication machinery to completely replicate chromosome termini (telomeres) leads to the progressive shortening of chromosomes upon continuous cell division (5). This shortening can ultimately lead to loss of telomeric function and chromosome destabilization. A DNA polymerase called telomerase is required to overcome the end replication problem. Unlike other DNA polymerases, telomerase is a ribonucleoprotein (RNP) composed of an essential RNA and a few proteins (6,7). It synthesizes the G-rich tandem repeats that comprise telomeres [(TTAGGG) 150-2000 m humans], using a template on the RNA that is complementary to the telomeric repeat. The interest of cancer researchers was aroused when it was proposed that telomerase is not expressed in human somatic tissues and that telomerase is required for cancer cell growth (8). The telomere hypothesis, as it has come to be called, states that telomerase is only active in the germline cells of adult humans (9-11), where it would be required to ensure the transmission of intact (i.e., full-length) chromosomes to progeny. In contrast, the telomeres of somatic cells would shorten until they reach a length that signals a halt to cell division (senescence). Studies in vitro suggest this barrier, called Ml, can be bypassed by transformation with viral oncogenes like SV40 T-antigen (12). However, the telomeres of cells at this point are still functional; but the cells are also telomerase negative, their telomeres continue to shorten, and the cells are not immortal (i.e., capable of indefinite division). Eventually transformed cells enter a second crisis, called M2, where the majority of the cells senesce and later die. In M2, telomere length has decreased to the point where a subset of the chromosomes have nonfunctional telomeres. Only rare cells that have undergone a specific mutational event(s) emerge from M2 and are immortal, and only these cells have stable telomeres and express telomerase (12). Thus, the nonexpression of telomerase in somatic tissues provides a barrier to indefinite cell growth, a supposed hallmark of cancer cells. Inhibition of telomerase in cancer cells might activate the cellular senescence pathway and prevent their propagation. Numerous studies of telomere length with donor tissues and a variety of primary (mortal) cell lines lend credibility to the model (13-15). Direct measurements of telomerase activity in tumor cells have also supported this theory. A study last year (16) demonstrated telomerase activity in ovarian carcinoma (ascites) cells but not in normal ovarian tissues surrounding the tumors. The telomerase assay used in this study requires enough cells that application of the technique to other cancers is impractical. However, in what represents an important advance, a highly sensitive polymerase chain reaction-based assay for telomerase activity has been developed (1), and many normal human tissues and more than 400 tumor specimens and tumor cell lines have now been tested (7-3). Only testis and ovary express telomerase among somatic tissues, and more than 85% of tumors contain telomerase activity. By using this assay and the newly reported human telomerase RNA gene as a probe, it should be possible to examine other tumors for the presence of telomerase and to test the universality of these results. In the future, only direct measurements of telomerase activity or gene expression should be used, since inferring the presence of telomerase from measurements of telomere length is often misleading, based on the fact that comparisons of telomerase activity and telomere length in cell lines do not indicate that they are associated (1,17). While the evidence strongly supports the telomere hypothesis, only molecular genetic manipulation of the human telomerase RNA gene in cell lines will allow elucidation of the role that telomerase has in the escape from senescence. Many issues remain to be resolved. What role does cellular immortality have in cancer? Is telomerase activation necessary for cell immortalization? Will prevention or reversal of cancer cell immortality be an effective treatment, and can antitelomerase therapy prevent or reverse cell immortalization? What problems might be associated with this therapy, and what types of cancer would be amenable to this treatment? There are likely to be several barriers to obtaining cellular immortality, but one barrier is the chromosome end replication problem. The issue of whether cancer cells are immortal is un-