Telomerase and Cancer
Telomerase and Cancer
Telomeres consist of multiple repeats of a six-nucleotide sequence TTAGGG/CCCTAA at the ends of chromosomes. The purpose of telomeres appears to be the maintenance of the integrity of the ends of the chromosomes, not unlike the aglet at the end of your shoestring that keeps it from unraveling. The need for telomeres comes from a feature of DNA replication that endangers the end of the chromosome on the lagging strand. DNA replication involves the unwinding of the DNA helix. The leading strand is replicated in the 5’ to 3’ orientation in a long continuous fashion. The lagging strand is also replicated in the 5’ to 3’ orientation, but the synthesis of this strand occurs in short segments called Okazaki fragments. This discontinuous backstitching leaves the end of the lagging strand at risk of not being replicated, and, with each attempt at replication, a further shortening would occur, if not for telomerase. The telomerase recognizes the G-rich strand of the telomeric repeat and lengthens it in the 5’ to 3’ direction. The enzyme is a reverse transcriptase that carries an RNA template of the sequence it replicates; thus, its activity is not dependent upon having a complementary strand to use as a template.
In human germline cells (spermatozoa and oocytes), telomeres are about 15 kilobase pairs in length and telomerase expressed in these cells maintains the telomeres at a more or less constant length. By contrast, most somatic cells do not express telomerase and therefore, telomeres shorten with each replication and are shorter than telomeres in germ cells. This biologic feature of telomeres led some investigators to postulate that telomere shortening was the governor of cell replication and when telomeres got too short, senescence was the result. Telomeres were said to be a biologic clock. Aging, according to this notion, is caused by short telomeres.
Some data, however, were not consistent with the notion that telomere length was the crucial determinant of a cell’s ability to divide. For example, laboratory mice have telomeres that are about three times longer than those of humans;1 yet, their life-span, even in controlled environments, is only about two years, not three times the length of human life-span. Furthermore, senescent human cells have shorter telomeres than germ cells but telomeric sequences are still present in lengths similar to other eukaryotic organisms that continue to replicate.2 Thus, if telomere length is a biologic clock, it is certainly not an absolute one where getting down to 100 or so repeats signals replicative senescence in any cell type. Another concern about the telomere theory is how it could relate to aging processes in post-mitotic organs like the brain.
Nevertheless, the theory has had several boosts in the last few years. First, telomerase was found to be expressed in many types of cancers,3 a finding consistent with the theory that telomere shortening must be avoided in somatic cells attempting to become immortal. Indeed, some groups are now using the detection of telomerase as a means of detecting cancer in tissues and in effusions.4 Telomerase expression is said to be a prognostic factor in some tumors.5 A finding that is being held out as the coup de grace to skeptics of this theory was recently reported.6 Telomerase (the reverse transcriptase enzyme component) was inserted into normal retinal epithelial cells and foreskin fibroblasts and produced cells with a normal phenotype that proliferated in vitro for at least 20 doublings beyond the limit for normal telomerase nonexpressing cells. Telomeres lengthened in these cells and the expression of senescence-related proteins was inhibited. The cells were not neoplastic; they just continued to proliferate beyond the time when they would normally stop. Game over, according to the theory’s proponents.
But, some bothersome data that do not fit the theory remain. Kang and colleagues reported that normal human oral keratinocytes contained telomerase activity and proliferated well in vitro, and, when the cells lost telomerase activity, they underwent replicative senescence.7 This is clearly consistent with the telomere theory. However, the replicative senescence came without any measurable decrease in telomere length. How can senescence appear independent of telomere length if telomere length is crucial? It would seem that the only way to explain this result is if telomerase has some important replication-supporting activity independent of its influence on telomere length. Finally, telomerase knockout mice have been created that appear to have a completely normal life-span, and the cells of these mice are capable of being transformed into neoplastic cells that behave just like tumor cells that express telomerase.8 We have previously noted that mice may be different than other species, but these data are difficult for the telomerase theory advocates to explain away.
Regardless of whether telomere shortening is a determinant of the aging process, it is clear that developing a treatment aimed at inhibiting telomerase activity would be of interest to test as an anticancer agent. Other important data about telomeres need to be collected. Do telomeres really shorten with age in a person? Are telomeres shorter in sun-exposed skin than in sun-protected skin? Does the expression of telomerase in lymphocytes explain why a 65-year-old man vaccinated against small pox as a baby remains immune to it? Are there any disease states that are manifestations of premature shortening of telomeres? It will be of interest to watch as this field develops further. It is my prediction that there are interesting twists and turns that are yet to be found and that the theory that telomere shortening is central to aging and telomere maintenance crucial to neoplasia is far from proven.
References
1. Kipling D, Cooke HJ. Nature 1990;347:400.
2. Harley CB, et al. Nature 1990;345:458.
3. Kim NW, et al. Science 1994;266:2011.
4. Yang C-T, et al. J Clin Oncol 1998;16:567.
5. Hiyama K, et al. J Natl Cancer Inst 1995;87:895.
6. Bodnar AG, et al. Science 1998;279:349.
7. Kang MK, et al. Cell Growth Differ 1998;9:85.
8. Blasco MA, et al. Cell 1997;91:25.
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