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Cancers
Special Issues
The Role of Telomeres and Telomerase in Cancer
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The Role of Telomeres and Telomerase in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 86967

Special Issue Editor

Prof. Dr. Anita De Rossi

E-Mail Website
Guest Editor
Department of Surgery, Oncology, and Gastroenterology, Section of Oncology and Immunology, University of Padova, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata, 6435128 Padova, Italy
Interests: telomere; telomerase; telomere/telomerase in tumorigenesis; viral oncology; viral-driven malignancies in the immunocompromized host; pediatric HIV/AIDS

Special Issue Information

Dear Colleagues,

The telomere/telomerase complex is the key element that determines unlimited replicative potential, a hallmark of cancer cells. Telomere shortening, which occurs at each round of cell division, restricts cell proliferation and induces cell senescence and apoptosis in checkpoint-proficient normal somatic cells. Telomere erosion in checkpoint-compromised cells promotes genetic instability, a critical event in carcinogenesis. Genetic and/or epigenetic re-activation of telomerase, which maintains telomere length, grants cells unlimited proliferative capacity. Thus, telomere/telomerase interplay has a critical role in tumor initiation and progression, making this complex an attractive therapeutic target.

Several studies have demonstrated that neoplastic cells have shorter telomeres than their adjacent non-neoplastic cell counterparts. A few recent studies indicating that shorter telomeres in tumor-surrounding mucosa are prognostic of local recurrence may support the concept that a telomere-shortened epithelial cell population is a good marker of field cancerization, but the prognostic value of telomere length in tumors is still controversial.

While many studies have identified telomerase expression and/or activity in tumor cells as independent prognostic factors, very few studies have addressed the potential role of circulating telomerase levels for minimally invasive monitoring of neoplastic patients.

Moreover, accumulating evidence indicates that telomerase has extra-telomeric functions in tumor cell survival and proliferation. Targeting telomerase is not a new concept; however, there is still insufficient knowledge of the proteins, complexes, and signaling pathways that mediate the noncanonical functions of telomerase to effectively identify strategies that inhibit its tumor-promoting role(s).

In this Special Issue, we will focus on the novel aspects of telomere/telomerase biology that may translate into broader efficacy in cancer diagnosis and treatment.

Potential topics include but are not limited to the following:

  • Reactivation of telomerase in cancer, with particular focus on the hotspot mutations in the TERT promoter region and transcriptional activation by exogenous agents (e.g., viral proteins);
  • Diagnostic and prognostic value of telomerase expression and/or telomere length in tumor cells, adjacent mucosa, and peripheral blood compartments;
  • Extratelomeric functions of telomerase contributing to the tumorigenic process;
  • Identification of novel strategies for targeting telomerase in cancer, with a view to simultaneously disrupting noncanonical activities as well as telomere maintenance.

Prof. Anita De Rossi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • telomere
  • telomerase/TERT
  • prognostic markers
  • circulating TERT
  • field cancerization
  • targeted therapy
  • telomerase re-activation
  • telomerase functions
  • telomerase inhibition

Published Papers (18 papers)

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Research

Jump to: Review

21 pages, 2484 KiB  
Article
Analysis of TERT Isoforms across TCGA, GTEx and CCLE Datasets
by Mathushan Subasri, Parisa Shooshtari, Andrew J. Watson and Dean H. Betts
Cancers 2021, 13(8), 1853; https://doi.org/10.3390/cancers13081853 - 13 Apr 2021
Cited by 4 | Viewed by 3576
Abstract
Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are [...] Read more.
Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are further complicated by their highly diverse expression and nature. Our primary objective was to characterize TERT isoform expression across 7887 neoplastic and 2099 normal tissue samples using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx), respectively. We confirmed the global overexpression and splicing shift towards full-length TERT in neoplastic tissue. Stratifying by tissue type we found uncharacteristic TERT expression in normal brain tissue subtypes. Stratifying by tumor-specific subtypes, we detailed TERT expression differences potentially regulated by subtype-specific molecular characteristics. Focusing on β-deletion splicing regulation, we found the NOVA1 trans-acting factor to mediate alternative splicing in a cancer-dependent manner. Of relevance to future tissue-specific studies, we clustered cancer cell lines with tumors from related origin based on TERT isoform expression patterns. Taken together, our work has reinforced the need for tissue and tumour-specific TERT investigations, provided avenues to do so, and brought to light the current technical limitations of bioinformatic analyses of TERT isoform expression. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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15 pages, 3168 KiB  
Article
Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients
by Enrica Rampazzo, Erika Cecchin, Paola Del Bianco, Chiara Menin, Gaya Spolverato, Silvia Giunco, Sara Lonardi, Sandro Malacrida, Antonino De Paoli, Giuseppe Toffoli, Salvatore Pucciarelli and Anita De Rossi
Cancers 2020, 12(11), 3115; https://doi.org/10.3390/cancers12113115 - 25 Oct 2020
Cited by 12 | Viewed by 2156
Abstract
Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, [...] Read more.
Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1–19.1) and 3.0(1.3–6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9–17.8) and 5.3(1.4–19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1–0.9) and 0.3(0.1–0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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16 pages, 1922 KiB  
Article
Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish
by Silvia Giunco, Manuela Zangrossi, Francesca Dal Pozzolo, Andrea Celeghin, Giovanni Ballin, Maria Raffaella Petrara, Aamir Amin, Francesco Argenton, Miguel Godinho Ferreira and Anita De Rossi
Cancers 2020, 12(8), 2052; https://doi.org/10.3390/cancers12082052 - 25 Jul 2020
Cited by 8 | Viewed by 2903
Abstract
Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability [...] Read more.
Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability via telomeres’ length-independent mechanism. Here we evaluate the anti-proliferative and pro-apoptotic effects of short-term telomerase inhibition in vivo in wild-type (wt) and tert mutant (terthu3430/hu3430; tert−/−) zebrafish embryos, and in malignant human B cells xenografted in casper zebrafish embryos. Short-term Tert inhibition by BIBR in wt embryos reduced cell proliferation, induced an accumulation of cells in S-phase and ultimately led to apoptosis associated with the activation of DNA damage response; all these effects were unrelated to telomere shortening/dysfunction. BIBR treatment showed no effects in tert−/− embryos. Xenografted untreated malignant B cells proliferated in zebrafish embryos, while BIBR pretreated cells constantly decreased and were significantly less than those in the controls from 24 to up to 72 h after xenotransplantation. Additionally, xenografted tumor cells, treated with BIBR prior- or post-transplantation, displayed a significant higher apoptotic rate compared to untreated control cells. In conclusion, our data demonstrate that short-term telomerase inhibition impairs proliferation and viability in vivo and in human malignant B cells xenografted in zebrafish, thus supporting therapeutic applications of TERT inhibitors in human malignancies. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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17 pages, 2476 KiB  
Article
Comprehensive Assessment of TERT mRNA Expression across a Large Cohort of Benign and Malignant Thyroid Tumours
by Ana Pestana, Rui Batista, Ricardo Celestino, Sule Canberk, Manuel Sobrinho-Simões and Paula Soares
Cancers 2020, 12(7), 1846; https://doi.org/10.3390/cancers12071846 - 09 Jul 2020
Cited by 12 | Viewed by 2251
Abstract
The presence of TERT promoter (TERTp) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from [...] Read more.
The presence of TERT promoter (TERTp) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. TERT mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, TERT mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. TERTp mutations and TERT mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas TERT mRNA expression in the benign tumours is associated with the presence of thyroiditis. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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16 pages, 7776 KiB  
Article
Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns
by Alexandra Posch, Sarah Hofer-Zeni, Eckhard Klieser, Florian Primavesi, Elisabeth Naderlinger, Anita Brandstetter, Martin Filipits, Romana Urbas, Stefan Swiercynski, Tarkan Jäger, Paul Winkelmann, Tobias Kiesslich, Lingeng Lu, Daniel Neureiter, Stefan Stättner and Klaus Holzmann
Cancers 2020, 12(6), 1625; https://doi.org/10.3390/cancers12061625 - 19 Jun 2020
Cited by 3 | Viewed by 2933
Abstract
Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. [...] Read more.
Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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20 pages, 1462 KiB  
Article
TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma
by Dagmara Rusinek, Aleksandra Pfeifer, Marta Cieslicka, Malgorzata Kowalska, Agnieszka Pawlaczek, Jolanta Krajewska, Sylwia Szpak-Ulczok, Tomasz Tyszkiewicz, Monika Halczok, Agnieszka Czarniecka, Ewa Zembala-Nozynska, Mykola Chekan, Roman Lamch, Daria Handkiewicz-Junak, Aleksandra Ledwon, Ewa Paliczka-Cieslik, Aleksandra Kropinska, Barbara Jarzab and Malgorzata Oczko-Wojciechowska
Cancers 2020, 12(6), 1597; https://doi.org/10.3390/cancers12061597 - 17 Jun 2020
Cited by 17 | Viewed by 3092
Abstract
Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp [...] Read more.
Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(−) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs. Deregulation of pathways involved in key cell processes was observed. Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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21 pages, 4742 KiB  
Article
Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors
by Aurora Irene Idilli, Francesca Pagani, Emanuela Kerschbamer, Francesco Berardinelli, Manuel Bernabé, María Luisa Cayuela, Silvano Piazza, Pietro Luigi Poliani, Emilio Cusanelli and Maria Caterina Mione
Cancers 2020, 12(4), 1028; https://doi.org/10.3390/cancers12041028 - 22 Apr 2020
Cited by 8 | Viewed by 3367
Abstract
Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, [...] Read more.
Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, alternative lengthening of telomeres (ALT) is found in a subset of sarcomas and malignant brain tumors. ALT is a non-canonical mechanism of telomere maintenance developed by cancer cells with no-functional telomerase. Methods: To identify drivers and/or markers of ALT, we performed a differential gene expression analysis between two zebrafish models of juvenile brain tumors, that differ only for the telomere maintenance mechanism adopted by tumor cells: one is ALT while the other is telomerase-dependent. Results: Comparative analysis of gene expression identified five genes of the pre-replicative complex, ORC4, ORC6, MCM2, CDC45 and RPA3 as upregulated in ALT. We searched for a correlation between telomerase levels and expression of the pre-replicative complex genes in a cohort of paediatric brain cancers and identified a counter-correlation between telomerase expression and the genes of the pre-replicative complex. Moreover, the analysis of ALT markers in a group of 20 patients confirmed the association between ALT and increased RPA and decreased H3K9me3 localization at telomeres. Conclusions: Our study suggests that telomere maintenance mechanisms may act as a driver of telomeric DNA replication and chromatin status in brain cancers and identifies markers of ALT that could be exploited for precise prognostic and therapeutic purposes. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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19 pages, 4358 KiB  
Article
Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis
by Georgios D. Ayiomamitis, George Notas, Thivi Vasilakaki, Aikaterini Tsavari, Styliani Vederaki, Theodosis Theodosopoulos, Elias Kouroumalis and Apostolos Zaravinos
Cancers 2019, 11(10), 1536; https://doi.org/10.3390/cancers11101536 - 11 Oct 2019
Cited by 27 | Viewed by 4981
Abstract
Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important [...] Read more.
Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. Methods: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. Results: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Conclusions: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor’s stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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Review

Jump to: Research

19 pages, 1254 KiB  
Review
Role of POT1 in Human Cancer
by Yangxiu Wu, Rebecca C. Poulos and Roger R. Reddel
Cancers 2020, 12(10), 2739; https://doi.org/10.3390/cancers12102739 - 24 Sep 2020
Cited by 35 | Viewed by 5395
Abstract
Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate [...] Read more.
Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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16 pages, 834 KiB  
Review
Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy
by Adam Eckburg, Joshua Dein, Joseph Berei, Zachary Schrank and Neelu Puri
Cancers 2020, 12(9), 2337; https://doi.org/10.3390/cancers12092337 - 19 Aug 2020
Cited by 14 | Viewed by 4373
Abstract
Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its [...] Read more.
Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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23 pages, 332 KiB  
Review
Anti-Cancer Immunotherapies Targeting Telomerase
by Simone Negrini, Raffaele De Palma and Gilberto Filaci
Cancers 2020, 12(8), 2260; https://doi.org/10.3390/cancers12082260 - 12 Aug 2020
Cited by 33 | Viewed by 3474
Abstract
Telomerase is a reverse transcriptase that maintains telomeres length, compensating for the attrition of chromosomal ends that occurs during each replication cycle. Telomerase is expressed in germ cells and stem cells, whereas it is virtually undetectable in adult somatic cells. On the other [...] Read more.
Telomerase is a reverse transcriptase that maintains telomeres length, compensating for the attrition of chromosomal ends that occurs during each replication cycle. Telomerase is expressed in germ cells and stem cells, whereas it is virtually undetectable in adult somatic cells. On the other hand, telomerase is broadly expressed in the majority of human tumors playing a crucial role in the replicative behavior and immortality of cancer cells. Several studies have demonstrated that telomerase-derived peptides are able to bind to HLA (human leukocyte antigen) class I and class II molecules and effectively activate both CD8+ and CD4+ T cells subsets. Due to its broad and selective expression in cancer cells and its significant immunogenicity, telomerase is considered an ideal universal tumor-associated antigen, and consequently, a very attractive target for anti-cancer immunotherapy. To date, different telomerase targeting immunotherapies have been studied in pre-clinical and clinical settings, these approaches include peptide vaccination and cell-based vaccination. The objective of this review paper is to discuss the role of human telomerase in cancer immunotherapy analyzing recent developments and future perspectives in this field. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
24 pages, 1058 KiB  
Review
Telomeres and Telomerase in the Development of Liver Cancer
by Lena in der Stroth, Umesh Tharehalli, Cagatay Günes and André Lechel
Cancers 2020, 12(8), 2048; https://doi.org/10.3390/cancers12082048 - 24 Jul 2020
Cited by 31 | Viewed by 4510
Abstract
Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in [...] Read more.
Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage–fusion–bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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38 pages, 1893 KiB  
Review
Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential
by Stina George Fernandes, Rebecca Dsouza, Gouri Pandya, Anuradha Kirtonia, Vinay Tergaonkar, Sook Y. Lee, Manoj Garg and Ekta Khattar
Cancers 2020, 12(7), 1901; https://doi.org/10.3390/cancers12071901 - 14 Jul 2020
Cited by 31 | Viewed by 8322
Abstract
Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere [...] Read more.
Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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19 pages, 2715 KiB  
Review
Telomerase and CD4 T Cell Immunity in Cancer
by Magalie Dosset, Andrea Castro, Hannah Carter and Maurizio Zanetti
Cancers 2020, 12(6), 1687; https://doi.org/10.3390/cancers12061687 - 25 Jun 2020
Cited by 17 | Viewed by 4496
Abstract
Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play [...] Read more.
Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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Graphical abstract

17 pages, 1139 KiB  
Review
Telomerase Biogenesis and Activities from the Perspective of Its Direct Interacting Partners
by Kathryn T. T. T. Nguyen and Judy M. Y. Wong
Cancers 2020, 12(6), 1679; https://doi.org/10.3390/cancers12061679 - 24 Jun 2020
Cited by 13 | Viewed by 3326
Abstract
Telomerase reverse transcriptase (TERT)—the catalytic subunit of telomerase—is reactivated in up to 90% of all human cancers. TERT is observed in heterogenous populations of protein complexes, which are dynamically regulated in a cell type- and cell cycle-specific manner. Over the past two decades, [...] Read more.
Telomerase reverse transcriptase (TERT)—the catalytic subunit of telomerase—is reactivated in up to 90% of all human cancers. TERT is observed in heterogenous populations of protein complexes, which are dynamically regulated in a cell type- and cell cycle-specific manner. Over the past two decades, in vitro protein–protein interaction detection methods have discovered a number of endogenous TERT binding partners in human cells that are responsible for the biogenesis and functionalization of the telomerase holoenzyme, including the processes of TERT trafficking between subcellular compartments, assembly into telomerase, and catalytic action at telomeres. Additionally, TERT have been found to interact with protein species with no known telomeric functions, suggesting that these complexes may contribute to non-canonical activities of TERT. Here, we survey TERT direct binding partners and discuss their contributions to TERT biogenesis and functions. The goal is to review the comprehensive spectrum of TERT pro-malignant activities, both telomeric and non-telomeric, which may explain the prevalence of its upregulation in cancer. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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16 pages, 2016 KiB  
Review
The Role of Alternative RNA Splicing in the Regulation of hTERT, Telomerase, and Telomeres: Implications for Cancer Therapeutics
by Aaron L. Slusher, Jeongjin JJ Kim and Andrew T. Ludlow
Cancers 2020, 12(6), 1514; https://doi.org/10.3390/cancers12061514 - 10 Jun 2020
Cited by 14 | Viewed by 3498
Abstract
Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes [...] Read more.
Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesize de novo telomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates that hTERT alternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing of hTERT from the telomerase activity producing full-length hTERT isoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of the hTERT gene in various somatic and cancer cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide insight into new treatment strategies targeting hTERT in telomerase-positive cancers. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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15 pages, 1358 KiB  
Review
The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications
by Marta Recagni, Joanna Bidzinska, Nadia Zaffaroni and Marco Folini
Cancers 2020, 12(4), 949; https://doi.org/10.3390/cancers12040949 - 11 Apr 2020
Cited by 27 | Viewed by 5213
Abstract
Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative [...] Read more.
Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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29 pages, 3529 KiB  
Review
Telomeres and Telomere Length: A General Overview
by Nalini Srinivas, Sivaramakrishna Rachakonda and Rajiv Kumar
Cancers 2020, 12(3), 558; https://doi.org/10.3390/cancers12030558 - 28 Feb 2020
Cited by 138 | Viewed by 17394
Abstract
Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most [...] Read more.
Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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