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

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.

Anti-Cancer Immunotherapies Targeting Telomerase

“…Recently, comprehensive whole-genome analysis has identified that the accumulation of point mutations within the promoter region of the hTERT gene is responsible for the increased TERT expression [13]. Only in a minority of cancer, telomere length maintenance is achieved by telomerase-independent mechanisms, referred to as "alternative lengthening of telomeres" (ALT) [14].…”

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

“…Telomeric DNA ranges from 3 to 15 Kb in humans, leaving a G-rich 3'-single-strand extended beyond the complementary chain, usually called the G-overhang [1,2]. To avoid the end-protection problem due to the overhang chain, the G-tail folds into itself, invading the double-stranded telomeric DNA, forming a lasso-like structure called the t-loop [3], which is protected by a six protein complex called shelterin [4], essential for telomere replication and regulation [2,3]. The shelterin complex is composed of the telomeric repeat binding factors 1 and 2 (TRF1 and TRF2), which interact with the telomeric double-stranded DNA and the protection of telomeres 1 (POT1) that bind to the single-stranded DNA [5].…”

“…A high proportion of tumors reactivate the expression of telomerase to maintain its chromosomal ends, while 10-15% of human cancers use the ALT pathway [7]. ALT is frequently detected in tumors of mesenchymal or neuroephitelial origin [8], but there have been reports of the ALT mechanism detected in a fraction of epithelial tumors like: breast, skin, ovarian, uterus and gastric, among others [3,9].…”

“…Although, many ALT-related genomic alterations have been resolved, such as the loss of function of ATRX, DAXX, H3F3A, or the BIR-related pathways dependent or independent of RAD51 and RAD52 [1,7,10,15], the molecular basis through which ALT occurs remains elusive and poorly understood [7] Many anti-telomerase-based cancer therapies are believed to cause the switching in some tumors from telomerase to ALT [3,16]. Indeed, the co-existence of both telomerase-dependent and ALT mechanisms have been reported in different cancer types [3,17]. This evidence sheds light on ALT as a potential target for therapy, because of the poor prognosis associated with these cancer types [1,7,18].…”

“…Many anti-telomerase-based cancer therapies are believed to cause the switching in some tumors from telomerase to ALT [ 3 , 16 ]. Indeed, the co-existence of both telomerase-dependent and ALT mechanisms have been reported in different cancer types [ 3 , 17 ].…”