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Journal of Experimental & Clinical Cancer Research . 22 December 2017 .
Pompili L , Leonetti C, Biroccio A, Salvati E.Abstract :
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.
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The requirement for cancers to utilize a TMM begs the question whether such pathways can be targeted for clinical purpose. While telomerase targeting approaches have been pursued for years leading to clinical applications, the prognostic and therapeutic significance of ALT is still debated. The emerging complexity of ALT mechanisms can explain the heterogeneous behavior of ALT tumors in terms of disease progression and response to treatment. Therefore, the deep comprehension of the molecular mechanisms at the root of ALT pathways appears to be crucial for the identification of new surrogate markers for ALT diagnosis and for the development of target specific anticancer strategies.
The results of the present work confirmed that the c-circle presence is the most sensitive and reliable method to detect ALT mechanisms also in cells expressing a certain level of TA. Moreover, we firstly described an exceptional sensitivity of ALT+ cells to trabectedin, that correlated with c-circles expression degree. Being trabectedin a drug already employed in tumor histotypes with high ALT frequency, this findings strongly suggest that ALT diagnosis in cancer patients could be predictive of treatment response and consequently help in the therapeutic choice.
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