PerspectiveCANCER

Cancer and Telomeres—An ALTernative to Telomerase

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Science  15 Jun 2012:
Vol. 336, Issue 6087, pp. 1388-1390
DOI: 10.1126/science.1222394

To grow indefinitely, human cancer cells must counteract the progressive loss of telomeric DNA that universally accompanies cell division. To do this, about 85 to 90% of cancers use telomerase (13), an enzyme that synthesizes the tandem 5′-TTAGGG-3′ hexanucleotide repeats of telomeric DNA by reverse transcription using its own RNA subunit as a template. Because telomerase is not expressed in most normal human cells, telomerase inhibition is considered an almost universal oncology target, and several clinical trials are under way (4). However, the future success of inhibiting telomerase to treat cancer is far from assured. Indeed, ∼10 to 15% of human cancers lack detectable telomerase activity (3), and many of these use an alternative lengthening of telomeres (ALT) mechanism (5). These ALT-expressing tumors would not be expected to respond to anti-telomerase therapies, and telomerase-expressing tumors could become resistant by switching to an ALT mechanism, as has recently been shown in mice (6). Here we present a brief history of ALT research, outline what is left to learn about the pathway, and propose it as a valuable drug target both alone and in combination with telomerase as a dual-targeted anticancer strategy.

Because of the semiconservative mechanism whereby DNA is replicated, all cellular proliferation is accompanied by progressive telomere shortening. When telomeres become short, they elicit a DNA damage response that leads to the irreversible cell cycle arrest known as replicative senescence, which is a potent anticancer protection mechanism (7). Occasionally human cells acquire mutations that permit bypass of senescence to prolong proliferation. This results in telomeres that are so short that chromosome ends fuse together, leading to increased genomic instability, aneuploidy, and cell death. Rarely, the ensuing genomic changes result in engagement of a telomere maintenance mechanism (telomerase or ALT) and therefore unlimited proliferative potential, which contributes indirectly to the development of cancer (7).

In 1993 it was reported that yeast cells that survive deletion of telomerase activity are dependent on genes required for homologous recombination (8). In the following year, a small subset of human primary tumors (2) and immortalized cell lines (2, 9) was found to be telomerase-negative. Based on the yeast cell findings that telomere length can be maintained in the absence of telomerase, it was deduced that one or more alternative, telomerase-independent mechanisms exist in human cells (10). ALT involves copying of a telomeric template DNA via homologous recombination (see the figure). Cells that use ALT to overcome telomere shortening have many unusual characteristics (5, 10, 11), such as highly heterogeneous telomere lengths and abundant extrachromosomal telomeric DNA. Although we are beginning to understand some of the molecular details of ALT, there has not been any progress in developing anticancer therapeutics targeting the pathway. Moreover, the possibility of more than one ALT mechanism in human cells has not yet been ruled out.

Telomerase and ALT

In cancer cells, telomeres (red) may be lengthened by telomerase, which reverse transcribes the template region of its RNA subunit (hTR), or by ALT, in which a telomeric DNA template is copied. The template may be the telomere of a nonhomologous chromosome, or it could include extrachromosomal telomeric DNA in circular (illustrated) or linear form, another region of the same telomere via loop formation, or the telomere of a sister chromatid (11). A combination of telomerase and ALT inhibitors is predicted to be an effective strategy for treating cancer.

ALT occurs in a wide range of tumor types, and is a common telomere-lengthening mechanism in tumors such as osteosarcomas, undifferentiated pleomorphic sarcomas, leiomyosarcomas, astrocytic tumors grades 2 and 3, and pancreatic neuroendocrine tumors (11, 12). The clinical consequences of ALT require more detailed study, but appear to be highly dependent on tumor type, with a notably worse outcome for individuals who have ALT-positive liposarcomas and a better outcome for adults with ALT-positive glioblastoma multiforme (11). Presumably, the prognosis is dictated by the sum total of genetic changes associated with activation of ALT in a particular tumor type, rather than the telomere-lengthening mechanism alone. Future work will require the development of simple blood tests, such as the C-circle assay (13), to identify ALT-expressing cancers to better determine the prognostic value of ALT in a variety of cancers.

ALT is relatively rare in the most common types of cancers, carcinomas, which are derived from epithelia. One reason could be that some highly proliferative epithelial tissues normally express regulated levels of telomerase, which partially compensates for telomere shortening to permit the cellular proliferation required over a human lifetime. Therefore, during oncogenesis these cells may be more likely to maintain their telomeres by up-regulating telomerase expression than by engaging ALT. However, these cells could still engage ALT if telomerase is inhibited by drugs during cancer therapy.

How is ALT activated in some cancer cells? It was recently observed that ALT-positive pancreatic neuroendocrine tumors and tumors of the central nervous system have mutations in or lose normal expression of the ATRX or DAXX proteins, and/or histone H3.3 (14, 15). Because ATRX and DAXX act together to deposit H3.3 and remodel telomeric chromatin, it was proposed that this may block telomeric recombination and repress ALT, and that loss of function of these three proteins contributes to derepression of ALT (14, 15). It will be important to determine whether these changes are sufficient for activation of ALT or whether additional changes are required.

Telomerase is expressed in the great majority of malignant tumors (2, 3) and thus holds great promise as a critical and cancer cell–specific drug target. Indeed, there are several telomerase therapies in clinical trials, all of which are effective in the preclinical setting. These include the enzymatic activity inhibitor imetelstat (non–small cell lung cancer, multiple myeloma, and breast cancer, phase 2); an immunotherapy targeting telomerase epitopes expressed only on cancer cells (pancreatic cancer, phase 3); and a virotherapy that includes the hTERT promoter regulating critical adenoviral genes and thus only kills telomerase-positive cells (4). However, as with any targeted cancer therapy, the development of resistance is a potential threat, and malignancies that initially have only telomerase activity (i.e., the great majority) could become resistant to telomerase inhibitors by activating the ALT mechanism. In vitro experiments suggest that this is relatively uncommon, but the likelihood of resistance by this mechanism cannot be dismissed because the number of cells in typical cell culture experiments is many orders of magnitude lower than in clinically important tumors. In support of this conclusion, telomerase-positive T cell lymphomas arising in mice engineered to have telomeres of limiting length and from which telomerase activation was subsequently withdrawn entered a period of slow growth and then emerged with features of ALT (6). Another factor that will complicate treatment with telomerase inhibitors is that some tumors may have both telomerase and ALT activity (5, 11). This is at least in part due to intratumoral heterogeneity, and whether both telomere-lengthening mechanisms are sometimes spontaneously activated within the same cells is unknown. Continued growth of ALT-positive cells would likely make these tumors rapidly resistant to telomerase inhibitors.

While there continues to be high enthusiasm for developing better telomerase inhibitors, there appears to be less interest in academia and industry for targeting ALT. This is perhaps because it is much less common, and there is limited information about activation of ALT in telomerase-positive cancer cells treated with telomerase inhibitors (16). As more studies focus on the molecular details of ALT and the mechanism(s) involved in its engagement, specific molecular targets and vulnerabilities may be identified that lead to the development of ALT inhibitors. These, similar to telomerase inhibitors, could be effective targeted therapies for specific cancer subtypes. Strategies combining inhibitors of both telomerase and ALT may then prove to be the most powerful and durable anticancer approach (see the figure).

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