Key Points
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Telomerase activation or the cancer-specific, telomerase-independent alternative lengthening of telomeres (ALT) mechanism are two telomere maintenance mechanisms in human cells. Most prostate cancers activate telomerase and a subset of lethal metastases use ALT
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Substantial telomere shortening is common in prostate cancers and in the precursor lesion prostatic intraepithelial neoplasia (PIN). Moderate telomere shortening has also been observed in cancer-associated stroma
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The mechanisms for telomere shortening in prostate cancer and PIN are not fully understood; in addition to replication-associated telomere loss, inflammation and reactive oxygen species might be contributors
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Telomere length assessment might be useful in prostate cancer diagnosis and in current prognostic tools to more reliably predict whether organ-confined prostate cancer will progress to lethal metastatic disease
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Telomerase-targeted single-agent treatments for solid cancers have, to date, been ineffective in clinical trials; these therapies have yet to be tested in prostate cancer and might potentially be useful in combination with established androgen receptor (AR)-targeted treatments
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Disruption of AR function in AR-positive prostate cancer cells activates the DNA damage response (DDR) at telomeres; thus, DDR inhibitors might potentiate the effects of androgen deprivation therapy
Abstract
Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer-associated stromal cells correlated with lethal disease. Single-agent telomerase-targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer.
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Acknowledgements
The authors wish to thank Dr Christopher Michael Heaphy and Dr Karen Sandell Sfanos for critical reading of the manuscript. The authors' research work was supported by NIH research grants R01CA172380 to A. M., NIH Training in Areas Fundamental to Cancer Research 5T32CA009110-38 to M. K. G., and the Prostate Cancer Foundation Young Investigators Award (granted to C. M. Heaphy and supported M. K. G.).
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Glossary
- T-Loop
-
A structure stabilized by shelterin proteins at the end of telomeres, where the telomere double-stranded DNA loops onto itself to form a partial overlap between the 3′ G-rich telomere overhang and the complementary C-rich telomere strand upstream of the overhang.
- End replication problem
-
During DNA replication, synthesis on the lagging DNA strand of linear templates is incomplete, resulting in the loss of ∼50 terminal nucleotides in each round of cellular division.
- Replicative senescence
-
In normal cells, cessation of cell division owing to substantial telomere shortening following ∼50 cell divisions (Hayflick limit).
- BPH
-
Noncancerous enlargement of the prostate owing to hyperproliferation of epithelial and/or stromal cells in the prostate.
- Prostatic intraepithelial neoplasia
-
(PIN). A noncancerous lesion in the prostate with abnormal acinar architecture, observed as overcrowding of luminal cells with enlarged nuclei.
- High-grade PIN
-
(HGPIN). Considered a precursor lesion of prostate cancer, featuring cancer-like morphological abnormalities (for example, nuclear pleomorphism and prominent nucleoli), but no evidence of invasion.
- Reactive oxygen species
-
(ROS). Highly reactive, oxygen-containing free radicals that can damage cellular RNA, DNA, and proteins.
- 8-Oxoguanine
-
The best-characterized and highly abundant DNA lesion arising from the oxidation of guanine through reactive oxygen species.
- Base excision repair
-
(BER). The DNA repair pathway that employs specialized DNA glycosylases, N-glycosylase/DNA lyase and adenine DNA glycosylase, to repair 8-oxoguanine.
- G-Quadruplexes
-
Nucleic acid secondary structures arising from Hoogsteen base pairing (an alternative form of base pairing) interactions of guanine residues.
- Fragile sites
-
Unstable regions in the genome that are prone to break under replication stress.
- Prostatic inflammatory atrophy
-
Prostatic lesions characterized by increased proliferation and atrophic morphology of prostatic luminal epithelial cells, associated with local inflammatory cells.
- Chromothripsis
-
Multiple translocation events occurring in a single catastrophic event leading to imperfect rearrangement and repair of one or a few shattered chromosomes.
- Overdiagnosis and overtreatment
-
Diagnosing patients with a disease that will not give rise to symptoms or cause death, often leading to treatment that might have no benefit and might even be harmful to the patient.
- Fluorescence in situ hybridization
-
(FISH). A technique using fluorophore-conjugated oligonucleotide probes that bind to specific DNA sequences via complementary Watson–Crick base pairing, enabling detection of sequences of interest in intact cells or chromosomes by fluorescence microscopy.
- Prostate Cancer Prevention Trial
-
A study conducted from 1994–2003 to investigate if the 5α-reductase inhibitor finasteride reduces prostate cancer development in men ≥55 years of age.
- Peptide vaccine
-
A peptide conjugated with a vaccine adjuvant to stimulate an immune response against a target antigen that shares the same amino acid sequence of the peptide.
- Epithelial–mesenchymal transition
-
The biological process in which epithelial cells acquire characteristics more consistent with mesenchymal cells, including loss of cell polarity and adhesion, and enhanced migration and invasiveness.
- Telomere deprotection
-
Telomeres partially or completely unprotected by shelterin proteins, resulting in the activation of DDR.
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Graham, M., Meeker, A. Telomeres and telomerase in prostate cancer development and therapy. Nat Rev Urol 14, 607–619 (2017). https://doi.org/10.1038/nrurol.2017.104
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DOI: https://doi.org/10.1038/nrurol.2017.104
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