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. 2018 Feb 18;19(2):606.
doi: 10.3390/ijms19020606.

Telomere Length Maintenance in Cancer: At the Crossroad Between Telomerase and Alternative Lengthening of Telomeres (ALT)

Free PMC article

Telomere Length Maintenance in Cancer: At the Crossroad Between Telomerase and Alternative Lengthening of Telomeres (ALT)

Marco De Vitis et al. Int J Mol Sci. .
Free PMC article


Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation-both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM.

Keywords: alternative lengthening of telomeres (ALT); cancer; cancer therapy; telomerase; telomere.

Conflict of interest statement

The authors declare no conflicts of interest.


Figure 1
Figure 1
A proposed model for telomere maintenance mechanism (TMM) switching in epithelial cancer cells from telomerase-positive (Tel+) to alternative lengthening of telomeres (ALT)-positive (ALT+). (a) A cell of a Tel+ tumor with epithelial origin undergoes genetic and/or epigenetic modifications (coupled or not with epithelial-to-mesenchymal transition (EMT)), resulting in the loss of an ALT repressor and in the activation of a telomerase inhibitor, developing an ALT+ subpopulation. An antitelomerase therapy kills the Tel+ population, selecting ALT as the main TMM and turning the tumor in ALT+; (b) A group of cells with epithelial (or mesenchymal) origin undergo early genetic and/or epigenetic modifications resulting in the loss of an ALT repressor and reactivation of telomerase, leading the development of a tumor characterized by both telomerase and ALT coexistence within the same cells. The application of an antitelomerase therapy can suppress telomerase, leaving ALT as the only TMM in the tumor. The possibility of ALT+ to Tel+ transition in tumor of mesenchymal origin can be hypothesized but are not documented because ALT-targeting drugs are currently not available.

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