Abstract
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.
Highlights
One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM)
Unprotected telomeres, that are not bound to Shelterin, result in end-to-end chromosome fusions as the uncapped chromosome ends are recognized as double strand break (DSB) and joined together by classical or alternative non-homologous end joining pathways (NHEJ) pathways [2]
It should be noted that not all cancers appear to utilize a TMM: Cell lines derived from highly aggressive neuroblastomas were found to start off with long telomeres and experience continuous telomere shortening over 200 population doublings [8]
Summary
Telomeres are nucleoprotein complexes that cap the ends of linear chromosomes. Telomeric DNA is made up of hexanucleotides repeats, mainly 50 -TTAGGG-30 , and has a double-stranded portion (ranging from 5 to 12 kb in humans) which terminates in a single-strand overhang of the TTAGGG strand, often referred to as the G-overhang. It should be noted that not all cancers appear to utilize a TMM: Cell lines derived from highly aggressive neuroblastomas were found to start off with long telomeres and experience continuous telomere shortening over 200 population doublings [8]. The idea that telomerase repression is the reason behind ALT activation has been reinforced by experiments on cells derived from telomerase positive tumors. ALT-like phenotypes have been observed following telomerase inhibition in the colon-derived HCT15 cell line [14], on T-cell lymphoma cells in mice [15] and on human esophageal cancer cells [16]. A gene expression signature capable of distinguishing telomerase positive from ALT in cell lines and LPS samples has been uncovered [17]; the signature contains a regulatory signaling network involving repression of the telomerase reverse transcriptase (hTERT in humans). It is worth mentioning that some malignancies such as neuroblastomas [21] and osteosarcomas [22] exhibit intra-tumoral heterogeneity relative to TMMs, with some cells as telomerase positive and others displaying a typical ALT phenotype
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