Telomere length, telomeric proteins and genomic instability during the multistep carcinogenic process
Introduction
Human telomeres consist of non-coding DNA at the ends of chromosomes, involving several tandem TTAGGG repeats. Despite the high efficiency of the DNA replication machinery, telomeric DNA is not fully replicated; about 50–200 base pairs are lost every time a somatic human cell divides [1], [2]. Eventually, telomeres become too short, blocking any possibility of further cell proliferation. Indeed, this phenomenon – a potential protection mechanism against cancer, known as replicative senescence – usually takes place after about 50 population doublings and involves a permanent p53-dependent cell cycle arrest in G1 [3]. One single short telomere (or one unprotected telomere) may be sufficient to induce replicative senescence in normal cells, which consequently blocks their proliferation [4]. This observation suggests that telomeres act as an intracellular ‘timer’ limiting the number of mitotic cycles. However, if this checkpoint is bypassed through p53 or pRb inactivation [5], the cell can divide further, resulting in extensive telomere attrition. In such cases, it is possible that telomeres lose their protective functions, allowing chromosomal fusions and “breakage-fusion-bridges” (BFB) cycles [6], which can lead to chromosome imbalance, gene amplification, non-reciprocal translocation (a hallmark feature in solid tumors) and altered genetic expression. These events induce a DNA damage cellular response, resulting in a “crisis” state and cell death in most cases. Telomeres participate in various aspects of cell physiology and viability, such as chromosome stability and the transcriptional activity of nearby genes. Telomeres are also involved in chromosomal nuclear localization, segregation during the anaphase, homologous recombination in meiotic cells and the repair of DNA double strand breaks [4]. Numerous mechanisms and regulatory pathways have been implicated in telomere biology, demonstrating the importance of telomere homeostatic regulation. Therefore, with the observation of most of the above-mentioned mechanisms in cancer cells, telomeres may play a central role in cancer progression.
In embryonic cells and stem cells, telomere length is maintained by activation of a specialized catalytic complex called telomerase. Telomerase – before its inactivation during embryonic development – elongates the telomere at each cell division, despite the presence of several bound protective proteins. The multiprotein complex bound to the telomeres, termed shelterin [7], has fundamental roles in the regulation of telomere length and function. Shelterin, in cooperation with other proteins, participates in telomere homeostasis by folding DNA into a three-dimensional structure that protects telomeres from degradation, from inducing a double strand break (DSB)-like response, and from abnormal telomerase activity in normal tissues.
In this review, we discuss mechanisms underlying telomere shortening, modification of the production of telomeric proteins and associated genomic instability observed during the earliest stages of carcinogenesis. We will also focus on current techniques that allow detection and quantification of various telomere markers, which are altered during tumor progression.
Section snippets
Cancer is a multistep process
Carcinogenesis is a multistep and multi-focal process, characterized by stepwise accumulation of genetic and molecular abnormalities. These events generally follow exposure to carcinogens and result in the selection of clonal cells with uncontrolled growth capacities [8]. For instance, between 10 and 20, or more, genetic events appear to be necessary for lung carcinogenesis. Thus, cancer develops through a series of stepwise events, from preinvasive histological changes to invasive disease [9].
Telomere homeostasis is tightly controlled by telomeric proteins and the telomeric environment
In mammalian cells, the telomeric hexanucleotide tandem repeat sequence, TTAGGG, spans over a length of between about 5 and 15 kb. It ends with a G-rich 30-bp single-stranded 3′ overhang, which is evolutionarily conserved among eukaryotes [14], [15].
Telomeres are less strongly associated to nucleosomal proteins than non-telomeric chromatin, and have a different spacing. However, telomeres are strongly associated with telomere-specific proteins [16], [17]. Some of these proteins associate
Telomere length in multistep carcinogenesis
According to De Marzo and colleagues, telomere length abnormalities are nearly universal in preinvasive stages of human epithelial carcinogenesis. Indeed, telomere shortening occurs in most cases (88.6%) of early stage bladder, cervix, colon, oesophagal and oral cavity cancer [41]. Similar results were found for prostate cancer; 93% of high-grade prostatic intraepithelial neoplasia (HGPIN) lesions examined had much shorter telomeres than adjacent, apparently normal epithelial cells. This was
Tools evaluating genomic instability
As discussed, cancer development is a slow process involving the accumulation of genetic and molecular abnormalities. We have discussed the fact that genomic instability is present as a universal event early in the carcinogenic multistep process. This genomic instability is, at least partially, due to telomere attrition, which is in turn a source of novel genetic mutation. Because of its early apparition and role in cancer development, the evaluation of genomic instability has become one of the
Perspectives and conclusions
It is now widely accepted that telomere length acts as an intracellular timer, limiting cell replication. By critical shortening or capping deficiency, telomeres limit cell proliferation. Indeed, critically short or unprotected telomeres are recognized as double strand breaks and activate the H2AX–ATM–Chk2 pathway, inducing subsequent senescence via P53/Rb [83]. This phenomenon has been referred to as the first anticancer barrier [78], [79]. In addition, many studies clearly identify
Reviewers
Dr. Fabrizio D′Adda Di Fagagna, FIRC Institute of Molecular Oncology Foundation IFOM Foundation, Via Adamello 16, Milan I-20139, Italy.
Dr. Predrag Slijepcevic, Senior Lecturer, Brunel University, Brunel Institute of Cancer Genetics and Pharmacogenomics, Kingston Lane, Uxbridge, Middlesex UB8 3PH, United Kingdom.
Acknowledgements
The work in the L.S. laboratory was supported by TELINCA and RISC-RAD contract number FI6R-CT2003-508842. Christophe Raynaud is a doctoral fellow funded by CEA-Lilly fellowship.
Christophe M. Raynaud is currently a Ph.D. student at University of Paris XI. After graduation as an engineer from ESIL (Ecole Superieur d’Ingénieur de Luminy), he joined the Laboratory of Radiology and Oncology in Fontenay-aux-Roses, France to realise is Ph.D. under the direction of Pr. Jean-Charles Soria. He works on the role of telomeres, telomeric protein and DNA damage repair along multistep carcinogenesis. He works in collaboration with the Institut Gustave Roussy, Villejuif, France.
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Fatty acids and telomeres in humans
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2020, Fertility and SterilityPatterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer
2019, Clinical Breast CancerCitation Excerpt :Cancer cells maintain telomere stability primarily by producing telomerase enzyme, which counter-balances the telomere attrition processes during the trajectory of cancer development. Telomere shortening and telomerase activation in malignant tumor tissue were considered as risk factors for cancer initiation.20 In our study, 25% of cases showed lesser TL even though hTERT gene expression was high.
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Christophe M. Raynaud is currently a Ph.D. student at University of Paris XI. After graduation as an engineer from ESIL (Ecole Superieur d’Ingénieur de Luminy), he joined the Laboratory of Radiology and Oncology in Fontenay-aux-Roses, France to realise is Ph.D. under the direction of Pr. Jean-Charles Soria. He works on the role of telomeres, telomeric protein and DNA damage repair along multistep carcinogenesis. He works in collaboration with the Institut Gustave Roussy, Villejuif, France.
Laure Sabatier received her Ph.D. in Human Genetics (Paris VI) in 1988; she worked on the characterization of chromosome damages after heavy ion irradiation and described the occurrence of de novo chromosomal instability (telomere associations, chromosome imbalances) as long-term consequences of irradiation of human primary fibroblast. Her main interests are telomere processing, bypass of the senescence process and the role chromosome instability in the occurrence of chromosome imbalances detected in radiation-induced tumors. She has published approximately 100 papers in peer-review international journals and several books. Involved in several European Project since 1992, during FP5 she coordinated two contracts on Telomere and Radiosensitivity and currently she coordinates the running FP6 Integrated project RISC-RAD (radiosensitivity of individuals and susceptibility to cancer induced by ionizing RADiations) in Radioprotection Euratom. She is currently the head of Radiobiology and Oncology Unit in Life Science division at Atomic Energy Commission (CEA).
Ophélie Philipot is currently a Ph.D. student at University of Paris XI. She graduated in 2005 as an engineer by ESIL (Ecole Superieur d’Ingenieur de Luminy). Her Ph.D. is based on the study of epigenetic mechanisms and siRNA interference in proliferation genes in transdifferentiated tumor cells. She is working under the direction of Sliman Ait-Si-Ali in laboratory of epigenetic and cancer CNRS FRE2944, Villejuif, France. The end of her Ph.D. is predicted for November 2008.
Ken A. Olaussen received his Master of Science degree in genetics from the University of Oslo. He worked as an engineer in the private biotechnology sector (immuno-designed molecules) in Paris before he started his research on predictive factors of response to chemotherapy at the laboratory of radiobiology and oncology in Fontenay-aux-Roses, France (Laure Sabatier's lab) where he was part of the team that validated ERCC1 as a determinant of adjuvant chemotherapeutic efficacy in lung cancer. He received his doctorate diploma in cancerology from the University of Paris XI. He now receives his postdoctoral training at the Institut Gustave Roussy in Villejuif, France (Guido Kroemer's lab), where he investigates genetic instability and polyploidy in the genesis of colon and lung cancer. He also continuously collaborates with Pr. Jean-Charles Soria in his research on biological effects of targeted anticancer therapies in lung cancer.
Jean-Charles Soria is a Full Professor of Medicine and Medical Oncology at Paris University XI. He is a tenure-track and full time cancer specialist at Institut Gustave Roussy. Dr. Soria trained as a medical oncologist and obtained a Silver medal from Paris Medical School in 1997. He gained a Ph.D. degree in the fundamental basis of oncogenesis in 2001, and completed his training with a 2-year post-doctoral fellowship in the Department of Thoracic Head and Neck Medical Oncology at MD Anderson Cancer Center, Houston, USA. Professor Soria is currently head of the phase I programme at Institut Gustave Roussy and member of the lung cancer unit with a focus on targeted therapies. His main research interests are: early clinical development, pharmacodynamic biomarkers, early phase II trials and lung cancer. He is also involved in translational research aspects related to tumor progression notably in lung cancer models. He has authored a dozen manuscript on the role of telomerase in tumor progression. He has contributed to over a 130 peer-reviewed publications, including publications as first or last author in the New England Journal of Medicine, the Journal of the National Cancer Institute, Cancer Research and Clinical Cancer Research.