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Telomeres, Telomerase and Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 30044

Special Issue Editor


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Guest Editor
Institute of Molecular Biology and Pathology, National Research Counsil, Via degli Apuli, 4-00185 Rome, Italy
Interests: telomeres; cancer; poly-ADP ribosylation; G-quadruplex

Special Issue Information

Dear Colleagues,

Telomeres are terminal structures at the end of eukaryotic chromosomes deputed to the safeguard of genome stability. They consist of G-rich double stranded DNA repeats (in human TTAGGG) that terminate with a 5’ G-rich overhang. Telomeres are nucleoprotein structures where repeated DNA is covered by a six-members protein complex named shelterin. Shelterin proteins protect nucleic acid from enzymatic attack and attenuates DNA damage signalling generated by DNA ends exposure. The progressive erosion of telomeric repeats over rounds of DNA duplication determines senescence of adult somatic cells and represents an intrinsic barrier to cell transformation. Cancer cells overcome replicative senescence by re-activating telomere maintenance mechanisms, mainly telomerase activity and, in a residual percentage of tumors, ALT activity. Recent advances on the comprehension of telomere regulation and metabolism, unveil multiple cross-talks between telomere biology and cancer initiation and progression and strengthen the concept that telomeres components and telomere maintenance mechanisms could represent validated targets for cancer therapy.

In agreement with this, telomerase inhibitors are currently in clinical trials and telomeric proteins and DNA secondary structures (such as G-quadruplexes), are under pre-clinical evaluation as targets in anti-cancer therapy.

A deep knowledge of the impact of telomere homeostasis in different human cancers is of high relevance in pharmacological intervention against cancer. To this aim, this issue focuses on the role of “telosome” elements in cancer progression and as potential targets for cancer therapy. Authors are encouraged to submit relevant basic and translational research articles and review articles on this specific issue. 

Dr. Erica Salvati
Guest Editor

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Keywords

  • telomeres
  • telomerase
  • cancer
  • cancer therapy
  • telomeric G-quadruplexes

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Published Papers (4 papers)

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Research

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19 pages, 2491 KiB  
Article
Telomere and Telomerase-Associated Proteins in Endometrial Carcinogenesis and Cancer-Associated Survival
by Lucy Button, Bryony Rogers, Emily Thomas, Alice Bradfield, Rafah Alnafakh, Josephine Drury and Dharani K. Hapangama
Int. J. Mol. Sci. 2022, 23(2), 626; https://doi.org/10.3390/ijms23020626 - 6 Jan 2022
Cited by 6 | Viewed by 5727
Abstract
Risk of relapse of endometrial cancer (EC) after surgical treatment is 13% and recurrent disease carries a poor prognosis. Research into prognostic indicators is essential to improve EC management and outcome. “Immortality” of most cancer cells is dependent on telomerase, but the role [...] Read more.
Risk of relapse of endometrial cancer (EC) after surgical treatment is 13% and recurrent disease carries a poor prognosis. Research into prognostic indicators is essential to improve EC management and outcome. “Immortality” of most cancer cells is dependent on telomerase, but the role of associated proteins in the endometrium is poorly understood. The Cancer Genome Atlas data highlighted telomere/telomerase associated genes (TTAGs) with prognostic relevance in the endometrium, and a recent in silico study identified a group of TTAGs and proteins as key regulators within a network of dysregulated genes in EC. We characterise relevant telomere/telomerase associated proteins (TTAPs) NOP10, NHP2, NOP56, TERF1, TERF2 and TERF2IP in the endometrium using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). qPCR data demonstrated altered expression of multiple TTAPs; specifically, increased NOP10 (p = 0.03) and reduced NHP2 (p = 0.01), TERF2 (p = 0.01) and TERF2IP (p < 0.003) in EC relative to post-menopausal endometrium. Notably, we report reduced NHP2 in EC compared to post-menopausal endometrium in qPCR and IHC (p = 0.0001) data; with survival analysis indicating high immunoscore is favourable in EC (p = 0.0006). Our findings indicate a potential prognostic role for TTAPs in EC, particularly NHP2. Further evaluation of the prognostic and functional role of the examined TTAPs is warranted to develop novel treatment strategies. Full article
(This article belongs to the Special Issue Telomeres, Telomerase and Cancer)
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11 pages, 1988 KiB  
Article
Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism
by Ji-Yong Sung and Jae-Ho Cheong
Int. J. Mol. Sci. 2021, 22(20), 11101; https://doi.org/10.3390/ijms222011101 - 14 Oct 2021
Cited by 8 | Viewed by 2736
Abstract
Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types [...] Read more.
Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics. Full article
(This article belongs to the Special Issue Telomeres, Telomerase and Cancer)
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Review

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13 pages, 775 KiB  
Review
The Role of Telomerase in Breast Cancer’s Response to Therapy
by Eliza Judasz, Natalia Lisiak, Przemysław Kopczyński, Magdalena Taube and Błażej Rubiś
Int. J. Mol. Sci. 2022, 23(21), 12844; https://doi.org/10.3390/ijms232112844 - 25 Oct 2022
Cited by 15 | Viewed by 15885
Abstract
Currently, breast cancer appears to be the most widespread cancer in the world and the most common cause of cancer deaths. This specific type of cancer affects women in both developed and developing countries. Prevention and early diagnosis are very important factors for [...] Read more.
Currently, breast cancer appears to be the most widespread cancer in the world and the most common cause of cancer deaths. This specific type of cancer affects women in both developed and developing countries. Prevention and early diagnosis are very important factors for good prognosis. A characteristic feature of cancer cells is the ability of unlimited cell division, which makes them immortal. Telomeres, which are shortened with each cell division in normal cells, are rebuilt in cancer cells by the enzyme telomerase, which is expressed in more than 85% of cancers (up to 100% of adenocarcinomas, including breast cancer). Telomerase may have different functions that are related to telomeres or unrelated. It has been shown that high activity of the enzyme in cancer cells is associated with poor cell sensitivity to therapies. Therefore, telomerase has become a potential target for cancer therapies. The low efficacy of therapies has resulted in the search for new combined and more effective therapeutic methods, including the involvement of telomerase inhibitors and telomerase-targeted immunotherapy. Full article
(This article belongs to the Special Issue Telomeres, Telomerase and Cancer)
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18 pages, 1308 KiB  
Review
Telomere Targeting Approaches in Cancer: Beyond Length Maintenance
by Eleonora Vertecchi, Angela Rizzo and Erica Salvati
Int. J. Mol. Sci. 2022, 23(7), 3784; https://doi.org/10.3390/ijms23073784 - 29 Mar 2022
Cited by 16 | Viewed by 4684
Abstract
Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere [...] Read more.
Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different “telosome” components. Full article
(This article belongs to the Special Issue Telomeres, Telomerase and Cancer)
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