By Yun Son
Cancer has long been one of the biggest challenges in the medical and scientific fields. Although not always so, in many cases cancer is an age-related genetic disease, and is expressed only once genomic instability in cells is increased and the ability of replicative immortality is obtained. Telomeres are cap-like structures found at the end of chromosomes. These have a protective role as they prevent different chromosome ends from fusing together and from being recognised as sites of DNA damage. Normally, with successive cell divisions the length of telomeres shortens. Telomerases are enzymes that are found in a large number of cancer cells, and have a central role in maintaining telomere length. Recent studies have shown an important relationship between telomeres, telomerases and cancer, and this could lead to significant progress in the way we diagnose and treat cancer.
Telomeres are repetitive DNA-protein complexes that can be found at the end of chromosomes. They are formed by a specialised cap-like nucleoprotein structure that is made up itself of DNA and shelterin protein complexes. Dysfunctional telomeres are telomeres in normal somatic cells that have been critically shortened after numerous cell divisions. These can induce DNA damage responses (DDRs) that in turn evoke cellular senescence. In the case of abnormal cells that have undergone oncogenic changes however, cellular senescence can be evaded and cells can continue to divide. Once enough critically shortened telomeres are accumulated, telomere crisis is triggered – which results in extensive apoptosis. Some cells, however, can elude from this crisis and sustain short but stable telomere lengths and pursue cell growth. These cells eventually progress to a malignant phenotype.
Proliferative immortality in cancer cells is acquired by activation or upregulation of the human TERT gene (hTERT), which encodes telomerase. In normal cases this gene is silent. Telomerase is an enzyme that has reverse transcriptase activity when it forms a ribonucleoprotein enzyme complex with other proteins and functional RNA. In some rare cases, cells develop alternative lengthening of telomeres (ALT), a DNA recombination mechanism which can reverse telomere wearing, allowing the cells to maintain telomere length, evade senescence and obtain cell immortality. In 90% of human cancer cells the normally silenced hTERT is notably expressed. (Jafri et al., 2016)
The link between telomerases and telomeres and their role in cancer can be exploited to develop tumour suppressing mechanisms. For instance, telomere shortening in humans has two opposite effects on cancer, one of it being a tumour supressing effect. Whereas TERT activation upregulates telomerase activity, the silencing of it downregulates telomere activity in cells. Meaning, silencing of TERT diminishes telomerase activity and promotes shortening of telomeres, making it a tumour suppressor pathway. This, however, is not universal to all mammals, but only found in large animals necessitating a long lifespan for reproduction, such as humans or elephants. In lack of telomerases, human telomeres shorten at a rate of 50 to 100 bps per population doubling. Nonetheless, it is important to recall that telomere shortening has another opposite effect of promoting cancer, as loss of telomere protection can lead up to telomere crisis (Maciejowski & Lange, 2017).
Although gene therapy remains yet to be fully developed, the concept of it stands fairly positive. This consists of targeting cancer cells with a telomerase inhibitor. In theory, this should result in a shortening of telomeres after each successive cell division. After some time, the chromosomes will eventually become too unstable and the targeted cell would die. This would happen in all cells involved in the tumour and hopefully lead to tumour shrinkage. Gene therapy has great advantages and prospectives in terms of its efficacy, specificity and precision (Shay & Keith, 2008).
One example of a telomerase inhibitor is imetelstat. Imetelstat is a competitive telomerase inhibitor, which was introduced as an intravenous treatment for different cancers. It is especially known for its observed activity and effectiveness against cancer cell lines in mouse xenograft models in preclinical tests. The inhibitor showed great success inhibiting telomerase, thus shortening telomeres in numerous cancer cell lines, including those stemmed from the bladder, breast, lung, liver, prostate and pancreas. Imetelstat has been implemented into various clinical trials, and some of these trials have been successfully completed. Despite these successes, some had to be suspended, especially those in breast and lung cancer, because the United States FDA deferred them for haematological toxicity (Jafri et al., 2016).
Despite the great progress that has been made in the studies of telomeres, telomerases and their roles in cancer. There are still many underlying mechanisms, pathways and questions left that need to be answered and unearthed. The same goes for telomerase targeting therapeutic. Nonetheless, further research in this field could open doors to many effective ways to treat and diagnose cancer.
References:
Jafri, M. A., Ansari, S. A., Alaqhtani, M. H. & Shay, J. W. (2016) Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine. 8(1):69. Available from: https://genomemedicine.biomedcentral.com/track/pdf/10.1186/s13073-016-0324-x [Accessed 7th September 2020]
Maciejowski, J. & Lange, T. (2017) Telomeres in cancer: tumour suppression and genome instability. Natural Review Molecular Cell Biology. 18, 186. Available from: https://www.nature.com/articles/nrm.2016.171#citeas [Accessed 7th September 2020]
Shay, J. W. & Keith, W. N. (2008) Targeting telomerase for cancer therapeutics. British Journal of Cancer. 98, 677-683. Available from: https://www.nature.com/articles/6604209 [Accessed 8th September 2020]
Shay, J. W. & Wright, W. E. (2010) Telomeres and telomerase in normal and cancer stem cells. FEBS Letters. Vol. 58, Issue 17, 3819-3825. Available from: https://www.sciencedirect.com/science/article/pii/S0014579310004199 [Accessed 9th September 2020]
Imperial Bioscience Review 