Telomeres and telomerase may play a crucial role in cellular aging, cancer initiation, and tumor survival, but a thorough understanding of the mechanisms involved in telomere length (TL) maintenance and telomerase expression gives experts the tools they need to develop diagnostic tools, determine disease prognosis, and formulate effective anticancer therapeutics.
Telomeres and Telomerase: The Cancer Connection
Telomeres are specialized nucleoprotein structures that protectively cap the ends of the chromosomes to prevent them from fusing together and keep them from being identified as sites of DNA damage. They also contain the binding sites for the proteins responsible for maintaining genome integrity and the proliferative capacity of the cells.
Under normal conditions, the telomeres in human somatic cells gradually shorten as they undergo successive cell divisions (at a rate of 50 to 150 bp per cell division, although rates may vary between different cell lineages), until they reach a point where they are unable to cap the chromosomal ends. When this happens, the DNA damage responses (DDRs) are triggered and cell senescence (mortality stage 1 or M1) or extensive cell death (apoptosis) is initiated.
In some cases, cells with critically shortened telomeres bypass senescence and continue to proliferate until most ends are uncapped and crisis is initiated. This phase is usually characterized by genomic instability (point mutations, major rearrangements, and insertions/deletions) and extensive apoptosis.
Still, some cells with short yet stable telomeres evade crisis and gain immortality. Interestingly, the ribonucleoprotein telomerase is universally expressed in most of these cases.
Previous studies indicate that there are two mechanisms that help ensure the maintenance of the telomere length: (1) the transcriptional activation of telomerase (a telomere reverse transcriptase) and (2) the activation of alternative lengthening of telomeres (ALT), a DNA recombination telomere-independent mechanism that allows cells to bypass senescence by reversing telomere attrition. The majority (85% to 95%) of human cancer cells express telomerase, while 5% to 15% exhibit the activation of the ALT pathway.
Telomerase consists of telomerase reverse transcriptase or TERT (a catalytic protein subunit) and human telomerase RNA (hTR) or human telomerase RNA component (hTERC).
Aside from its role in maintaining telomere length, hTR plays a significant role in several oncogenesis-promoting processes, which include the synthesis of telomere DNA, assembly and localization of telomerase holoenzyme, regulation of gene expression, cell proliferation, DDR, and apoptosis. Moreover, hTR is also involved in cell adhesion and migration, epithelial–mesenchymal transition, WNT/β-catenin and NF-kB signaling, and MYC-driven oncogenesis.
While much is known about hTR’s role in oncogenesis, further research is needed to determine hTERT’s role in activating cancer cells and how it contributes to the progression of the disease. However, researchers observed two highly recurrent mutations within the core promoter region of hTERT (specifically at -124 bp and -146 bp upstream from the ATG start site) that may explain how telomerase is activated in cancer cells.
High frequencies of TERT promoter mutations are noted in some cancers including melanoma, liver cancer, carcinoma of the skin and urothelial cell carcinoma, glioma, pleomorphic dermal sarcoma, and myxoid liposarcoma while low frequencies were observed in gastrointestinal stromal tumors and gastric, pancreatic, and non-small-cell lung cancer.
Considering the fact that normal human cells have longer telomeres and significantly lower telomerase activity than cancer cells, experts have zeroed in on telomerase as a target for anti-cancer therapeutics development. Specifically, they are looking for ways to induce selective cell death and apoptosis in cancer cells without causing any untoward effects on normal cells.
In addition to the vaccines, antisense oligonucleotides (imetelstat), and telomerase inhibitors (BIBR1532) that have been developed to achieve this goal, researchers are still exploring and evaluating several treatment options (e.g. G-quadruplex stabilizers, tankyrase inhibitors, HSP 90 inhibitors, T-oligo, dendritic cell immunotherapy, hTERT and cryptic peptides) to selectively destroy cancer cells.