scholarly journals The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 949 ◽  
Author(s):  
Marta Recagni ◽  
Joanna Bidzinska ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Cancer Cells ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Limited Information ◽  
Adaptive Responses ◽  
Therapeutic Implications ◽  
Telomerase Inhibitors ◽  
Alternative Lengthening

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.

scholarly journals ALT: A Multi-Faceted Phenomenon

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 133 ◽  
Author(s):  
Aurore Sommer ◽  
Nicola J. Royle
Keyword(s):  
Molecular Markers ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Sequence Variation ◽  
Telomere Maintenance ◽  
Hallmarks Of Cancer ◽  
Telomere Elongation ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Made In

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

Role of Telomerase in Normal and Cancer Cells

2000 ◽  
Vol 18 (13) ◽  
pp. 2626-2634 ◽  
Author(s):  
Matthew Meyerson
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Detection ◽  
Telomeric Dna ◽  
Telomerase Inhibitors ◽  
Cell Immortalization ◽  
Detection And Diagnosis ◽  
And Function ◽  
Experimental Use

ABSTRACT: Shortening of the telomeric DNA at chromosome ends is postulated to limit the lifespan of human cells. In contrast, activation of telomerase, the enzyme that synthesizes telomeric DNA, is proposed to be an essential step in cancer cell immortalization and cancer progression. This review discusses the structure and function of telomeres and telomerase, the role of telomerase in cell immortalization, and the effects of telomerase inactivation on normal and cancer cells. Moreover, data on the experimental use of telomerase assays for cancer detection and diagnosis are reviewed. Finally, the review considers the evidence regarding whether telomerase inhibitors could be used to treat human cancers.

scholarly journals SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling

2021 ◽  
Vol 14 (689) ◽  
pp. eabe9613
Author(s):  
Nathaniel J. Robinson ◽  
Masaru Miyagi ◽  
Jessica A. Scarborough ◽  
Jacob G. Scott ◽  
Derek J. Taylor ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Intracellular Signaling ◽  
Binding Protein ◽  
Telomere Maintenance ◽  
Nucleocytoplasmic Shuttling ◽  
Iκb Kinase ◽  
Alternative Lengthening ◽  
Telomere Binding Protein ◽  
Sumo Ligase

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

scholarly journals Reciprocal impacts of telomerase activity and tumor cell differentiation in neuroblastoma tumor biology

2021 ◽  
Author(s):  
Eun Young Yu ◽  
Syed S Zahid ◽  
Sarah Aloe ◽  
Erik Falck-Pedersen ◽  
Xi Kathy Zhou ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Tumor Cell ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Growth Potential ◽  
Neuroblastoma Tumor ◽  
Telomere Protein ◽  
Mes Cells ◽  
Tumor Cell Differentiation

Telomere maintenance and tumor cell differentiation have been separately implicated in neuroblastoma malignancy. Their mechanistic connection is unclear. We analyzed neuroblastoma cell lines and morphologic subclones representing the adrenergic (ADRN) and mesenchymal (MES) differentiation states and uncovered sharp differences in their telomere protein and telomerase activity levels. Pharmacologic conversion of ADRN into MES cells elicited consistent and robust changes in the expression of telomere-related proteins. Conversely, stringent down-regulation of telomerase activity triggers the differentiation of ADRN into MES cells, which was reversible upon telomerase up-regulation. Interestingly, the MES differentiation state is associated with elevated levels of innate immunity factors, including key components of the DNA-sensing pathway. Accordingly, MES but not ADRN cells can mount a robust response to viral infections in vitro. A gene expression signature based on telomere and cell lineage-related factors can cluster neuroblastoma tumor samples into predominantly ADRN or MES-like groups, with distinct clinical outcomes. Our findings establish a novel mechanistic connection between telomere and differentiation and suggest that manipulating telomeres may suppress malignancy not only by limiting the tumor growth potential but also by inducing tumor cell differentiation and altering its immunogenicity.

Evidence for Alternative Lengthening of Telomeres in Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1179-1179
Author(s):  
Rajendra N. Damle ◽  
Taraneh Banapour ◽  
Cristina Sison ◽  
Steven L. Allen ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomerase Activity ◽  
Lymphocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Maintenance ◽  
Osteosarcoma Cell ◽  
Clonal Deletion ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
V Genes

Abstract Telomere shortening is a consequence of repetitive clonal replication and leads to clonal deletion unless DNA extension and repair occur. All tumors must circumvent this problem by up-regulating mechanisms that lead to chromosomal lengthening. Two mechanisms have been identified that maintain chromosome ends- telomerase that does so by reverse transcription and alternative lengthening of telomeres (ALT) that occurs by homologous recombination. The latter function is characterized by the presence of promyelocytic leukemia protein-associated nuclear bodies (PML-NBs) and the presence of PML-NB is used to mark cells that use this process. B cell Chronic lymphocytic leukemia (B-CLL) cells with unmutated Ig V genes have shorter mean telomere lengths compared with those exhibiting mutated Ig V genes. In addition, cells with unmutated Ig V genes demonstrate more telomerase activity than their mutated counterparts. The mutated cases show long and heterogeneously elongated telomeres in spite of the absence, in most cases, of detectable telomerase activity. Therefore we determined whether the ALT pathway plays a role in telomere maintenance in B-CLL, using a monoclonal anti-PML antibody and a flow-cytometric assay for assessment of PML protein. Telomerase-expressing Jurkat T cells and murine fibroblasts-L cells served as negative controls for PML staining, whereas the ALT positive Osteosarcoma cell line U2-OS served as a positive control. In a cohort of 20 B-CLL cases, PML protein was detected in all cases regardless of Ig V mutation status. In addition, a similar percentage of cells within the clones contained PML (10 - 90% of the members of unmutated clones and 11–96% of mutated clones), whereas peripheral blood B cells from 6/6 elderly normal donors did not show any PML staining. PML expression was compared with telomere length and telomerase activity in the same cases. The percentage of cells showing PML expression inversely correlated with telomerase activity (r= −0.58; p=0.029). Although in most published reports telomere maintenance by ALT occurs in the absence of telomerase activity, we found ALT (as suggested by PML positive cells) in cells with telomerase activity (detected by the standard TRAP assay). Thus, B-CLL cases can express PML bodies and some B-CLL cells can contain both PML-NB and express telomerase activity. These findings suggest that B-CLL cells can use two distinct mechanisms to assure telomere maintenance and perpetuate clonal survival and expansion.

Clinical Significance of Telomerase Activity in Gastric Carcinoma and Peritoneal Dissemination

2009 ◽  
Vol 37 (4) ◽  
pp. 1127-1138 ◽  
Author(s):  
X Hu ◽  
H Wu ◽  
S Zhang ◽  
H Yuan ◽  
L Cao
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Peritoneal Dissemination ◽  
Histological Grade ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cancer Antigen 125 ◽  
Amplification Protocol ◽  
Peritoneal Washings

Telomerase activity is responsible for telomere maintenance and is believed to be crucial in most cancer cells, but its significance in gastric cancer remains unknown. This observational study investigated whether there is a relationship between telomerase activity and the development of gastric cancer, and between telomerase activity and peritoneal dissemination. Telomerase activity was measured in primary gastric cancers and in peritoneal washings from the same patients, and findings were compared with those of conventional cytology and an immunoassay for cancer antigen 125 (CA125). Positive cytological examination and telomerase activity in peritoneal washings both correlated with the histological grade, depth of tumour invasion, area of serosal invasion and peritoneal metastasis. The detection of free cancer cells in peritoneal washings by the telomeric repeat amplification protocol/enzyme-linked immunosorbent assay (TRAP–ELISA) was significantly more sensitive than cytology or the CA125 immunoassay, suggesting that this could be used to diagnose early peritoneal dissemination.

scholarly journals Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timothy P. Lippert ◽  
Paulina Marzec ◽  
Aurora I. Idilli ◽  
Grzegorz Sarek ◽  
Aleksandra Vancevska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
A Cell ◽  
Infected Cells ◽  
Break Induced Replication ◽  
Alt Activity

AbstractTo achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

scholarly journals Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment

2021 ◽  
Vol 22 (3) ◽  
pp. 1476
Author(s):  
Gabriele Grasmann ◽  
Ayusi Mondal ◽  
Katharina Leithner
Keyword(s):  
Cancer Cells ◽  
Supply And Demand ◽  
Large Body ◽  
Metabolic Flexibility ◽  
Adaptive Responses ◽  
Vascular Networks ◽  
Extracellular Milieu ◽  
Normal Tissues ◽  
High Degree

The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented.

scholarly journals Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
M. Udugama ◽  
L. Hii ◽  
A. Garvie ◽  
M. Cervini ◽  
B. Vinod ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cancer Cells ◽  
Embryonic Stem ◽  
Telomere Maintenance ◽  
Histone Demethylases ◽  
Over Expression ◽  
Alternative Lengthening ◽  
Characteristic Features ◽  
Inactivating Mutations

AbstractAlternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase inactivated in ALT. Mouse embryonic stem cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B knockout or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. In this work, we demonstrate that inactivation of KDM4B, through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.

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