Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10–15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented.
MacNeil DE, Bensoussan HJ, Autexier C. Telomerase regulation from beginning to the end. Genes (Basel). 2016;7
Ulaner GA, Huang HY, Otero J, et al. Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma. Cancer Res. 2003;63:1759–63. PubMed
Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res. 1999;59:4175–9. PubMed
Koschmann C, Calinescu AA, Nunez FJ, et al. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med. 2016;8: 328ra328.
Muntoni A, Reddel RR. The first molecular details of ALT in human tumor cells. Hum Mol Genet. 2005;14 Spec No. 2: R191–R196.
Naderlinger E, Holzmann K. Epigenetic regulation of telomere maintenance for therapeutic interventions in gliomas. Genes (Basel). 2017;8
Cimino-Reale G, Gandellini P, Santambrogio F, Recagni M, Zaffaroni N, Folini M. miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an "ALT-like" phenotype in diffuse malignant peritoneal mesothelioma cells. J Hematol Oncol. 2017;10:140. CrossRefPubMedPubMedCentral
TY Y, Kao YW, Lin JJ. Telomeric transcripts stimulate telomere recombination to suppress senescence in cells lacking telomerase. Proc Natl Acad Sci U S A. 2014;111:3377–82. CrossRef
Sobinoff AP, Allen JA, Neumann AA, et al. BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. EMBO J. 2017;
Min J, Wright WE, Shay JW. Alternative lengthening of telomeres mediated by mitotic DNA synthesis engages break-induced replication processes. Mol Cell Biol. 2017;37
VandenBussche CJ, Allison DB, Graham MK, et al. Alternative lengthening of telomeres and ATRX/DAXX loss can be reliably detected in FNAs of pancreatic neuroendocrine tumors. Cancer. 2017;125:544–51. PubMed
Matsuo T, Shimose S, Kubo T, Fujimori J, Yasunaga Y, Ochi M. Alternative lengthening of telomeres as a prognostic factor in malignant fibrous histiocytomas of bone. Anticancer Res. 2010;30:4959–62. PubMed
Dorris K, Sobo M, Onar-Thomas A, et al. Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas. J Neuro-Oncol. 2014;117:67–76. CrossRef
Gowan SM, Heald R, Stevens MF, Kelland LR. Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol Pharmacol. 2001;60:981–8. PubMed
Greco C, Zupi G. Biological features and in vitro chemosensitivity of a new model of human melanoma. Anticancer Res. 1987;7:839–44. PubMed
- Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?
- BioMed Central
Journal of Experimental & Clinical Cancer Research
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