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

Marta Recagni,Joanna Bidzinska,Nadia Zaffaroni,Marco Folini

doi:10.3390/cancers12040949

Abstract

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.

Highlights

Telomeres are heterochromatic nucleoprotein complexes located at the termini of linear eukaryotic chromosomes [1]
The three main components are the telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), that bind to double-stranded telomeric DNA, and the protection of telomeres 1 (POT1), which binds directly to single-stranded telomeric sequences [1,2,3]
alternative telomere lengthening (ALT) status failed to affect clinical outcome, either using associated promyelocytic leukemia (PML) bodies (APB) (HR, 1.25; 95% CI, 0.54–2.89; p = 0.61) or telomere restriction fragment (TRF) analysis (HR, 0.57; 95% CI, 0.17–1.96; p = 0.38)

Summary

Introduction

Telomeres are heterochromatic nucleoprotein complexes located at the termini of linear eukaryotic chromosomes [1]. The three main components are the telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), that bind to double-stranded telomeric DNA, and the protection of telomeres 1 (POT1), which binds directly to single-stranded telomeric sequences [1,2,3] These proteins interact with additional factors, such as the TRF1-interacting protein 2 (TIN2), the ACD shelterin complex subunit and telomerase recruitment factor Owing to the incomplete synthesis of lagging strand DNA (i.e., the end-replication problem [2]), normal/premalignant dividing (i.e., mortal) cells progressively lose telomeric sequences This telomere shortening eventually results in dysfunctional uncapped telomeres in the improper chromosome end protection, which leads to the activation of a DNA damage response (DDR). The maintenance of telomere length and integrity has been described as an essential feature by which cancer cells attain replicative immortality (i.e., limitless lifespan) and stabilize their rearranged genomes [3,4]

Telomere Maintenance Mechanisms in Human Cancers

The Role of Telomere Maintenance Mechanisms in Tumors of Mesenchymal Origin

Findings

Conclusions