The subject of my last posting was the epigenetic clock. This one is about another biological mechanism for keeping time.
Way back in November 2018, I posted a short note (#43) entitled “Cancer Cell Immortality” in which I discussed the subject of chromosome ends and their relation to cancer and aging. Here’s a short summary.
Many decades ago the eminent biologist Leonard Hayflick discovered that most cells when placed into tissue culture have a limited life span, now known as the Hayflick Limit. It was subsequently found that his limit was due to the inability of the enzymes that synthesize DNA to replicate short sequences at the very ends of chromosomes. At each round of DNA replication, a normal cell loses a piece of the ends of all of its chromosomes. Without their normal ends, chromosomes begin to break and fuse, causing genetic instability and apoptosis. Ultimately, with continued division, there is further loss of DNA. Essential genes begin to be affected and the cells stop dividing.
Stem cells often need to divide past the Hayflick Limit and Nature has devised a clever way that allows them to do so. Its solution: telomeres, short (six base pairs, 5’ - TTAGGG - 3’) repetitive runs of DNA that are added to chromosome ends. A special enzyme, telomerase, adds more of the sequences whenever they run low, thereby allowing stem cells to replicate indefinitely.
Telomerase is a reverse transcriptase. That is, it uses an RNA as a template to synthesize a specific sequence of DNA. In this case, the enzyme (TERT) encloses a specific non-coding RNA (called TERC) in a pocket, makes a DNA copy of it, and appends the copy on to the chromosome ends as required (see illustration). The actual assembly of a functional telomere requires additional steps and enzymes, a discussion of which is beyond the scope of this posting.
Cancer cells, like stem cells and unlike their normal counterparts, can replicate indefinitely as evidenced by HeLa cells that have been grown in culture since 1951. While most normal cells have lost the ability to express telomerase, the cancer cells that derive from them have somehow regained the ability to make use of the enzyme. In fact, it is thought that 85-90% of all cancers have somehow managed to synthesize sufficient supplies of the telomerase enzyme so that they can divide indefinitely.
Given the near universal presence of telomerase in cancer cells and its almost complete absence in normal, non-stem, cells, it would seem that targeting telomerase might be a useful strategy to combat cancer. The idea would be to find an inhibitor of the enzyme, administer it to patients, stop cancer cells dividing, and voila, a cure for cancer. Several inhibitors have been tried, but most effort has gone into the development of vaccines against the enzyme.
What actually happens if you do try to inhibit telomerase? Are there adverse consequences? A total of twenty clinical trials, mostly phase I and II, have been conducted over the years and their results reviewed by Mizukoshi and Kaneko (1). They report that a variety of malignancies, including melanomas, prostate, breast, and pancreatic cancers were targeted with vaccines against telomerase. None showed adverse effects although it isn’t clear that if the therapy was continued for long period there might be. In most cases the investigators found that subjects mounted an immune response against the enzyme and, in some instances, survival rates increased modestly. The only trial that got to phase III, however, did not extend the lifespan of people with pancreatic cancer.
In sum, the good news is that therapies directed at telomerase are well tolerated; the bad is that they have had only limited success to date. Several explanations for the lack of progress have been advanced. Firstly, there is an alternative route to telomere lengthening (called appropriately ALT, alternative lengthening of telomeres). It may be that cancers can escape the effects of telomerase inhibitors by turning to this mechanism. Secondly, there is a reasonably long interval between application of an inhibitor and the death of the cancer cell. That’s because, cells need to divide multiple times in order for their telomeres to shorten enough so that the cells stop dividing. Finally, there’s the fact that stem cells require telomerase. And stem cells are needed throughout the body to rejuvenate tissues. If our stem cells are prevented from doing their job it’s likely that it won’t do our long term health any favors. It may well be that we might be able to check cancer by broadly inhibiting telomerase, but only at the expense of a shortened lifespan.
1. “Telomerase-Targeted Cancer Immunotherapy”, Eishiro Mizukoshi and Shuichi Kaneko, Int. J. Mol. Sci. 20: 1823 (2019).