Clinical Relevance of Alternative Lengthening of Telomeres in Cancer.

The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Moreover, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of the telomere. However, ALT has been implicated in different - sometimes opposite - outcomes, according to the tumor type studied. Then, in order to design and develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.

Long-term exposure to MST-312 leads to telomerase reverse transcriptase overexpression in MCF-7 breast cancer cells.

Telomerase is an enzyme responsible for telomere maintenance in almost all human cancer cells, but generally not expressed in somatic ones. Therefore, antitelomerase therapy is a potentially revolutionary therapeutic strategy, and the antitumor activity of telomerase inhibitors (TI) has been studied extensively recently, mainly for breast cancer. However, the effects expected from treatment with TI will appear only after many cell divisions, but the effects of this long-term approach are unknown. In this work, the consequences of 3120 h exposure of human breast cancer cells to TI MST-312 were investigated. MCF-7 cells were treated with MST-312 at a subtoxic concentration for a long time, and then cell morphology, viability, senescence, and proliferation were analyzed by phase-contrast microscopy, MTT assay, ß-galactosidase test, and the trypan blue exclusion assay, respectively. Also, chromosomal stability was evaluated by classical cytogenetic analysis. The average length of telomeres and telomerase reverse transcriptase expression were accessed by real-time PCR and real-time RT-PCR, respectively. The MST-312 showed cytotoxic action and promoted telomere erosion, senescence, and chromosome aberrations, as expected, but in a small proportion. Nevertheless, the proliferation rate of the culture was not affected. As the main effect, the chronic exposure led to cell adaptation by overexpression of telomerase in response to the inhibitor, which is a potential cause of therapeutic failure and may be associated with a poor prognosis. In conclusion, despite the high therapeutic potential of TIs such as MST-312, the molecular outcomes of long-term exposure of tumors on these drugs have to be evaluated when considering their clinical application, especially for breast cancer treatment.