Abstract
Prostate cancer exhibits diverse clinical behavior, a phenotypic reflection of the heterogeneous genetic and epigenetic aberrations underlying this disease. Recent work indicates that short, dysfunctional telomeres may be responsible for much of this genetic damage. Telomeres are essential DNA elements located at the ends of each chromosome. Telomeres shorten because of cell division and damage from reactive oxygen species, such as those elaborated by the inflammatory response. Recent studies indicate that abnormal telomere shortening occurs in the earliest phase of prostate tumorigenesis, at the pre-invasive prostatic intraepithelial neoplasia (PIN) stage, and that telomeres remain short in the majority of prostate adenocarcinomas. Thus, it is likely that telomere dysfunction plays a key role in both the initiation and progression of prostate cancer and evidence indicates that telomere length may have prognostic value.
Unlike normal prostate cells, prostate cancer cells activate the telomere maintenance enzyme telomerase, providing at least a minimal amount of stability to the shortened chromosomal ends. However, telomerase activity is subject to hormonal regulation, being downregulated during hormonal withdrawal; therefore, during androgen 1ablation therapy, the already shortened telomeres in prostate cancer cells may once again become unstable, leading to further genetic changes contributing to the development of androgen-independent disease. Apart from androgens, telomerase is also regulated in the prostate by the oncogene c-Myc, a gene frequently deregulated in prostate cancer.
The dependence of prostate cancer on telomerase activity makes this enzyme an attractive therapeutic target, and several strategies aimed at exploiting this dependence are currently under development.
In summary, short dysfunctional telomeres are likely to be major players in prostate cancer initiation and progression, as well as the development of hormone-refractory disease after androgen ablation. Measurement of telomere lengths or telomerase activity may provide valuable diagnostic and/or prognostic information. It is hoped that a thorough understanding of prostate cancer telomere biology will lead to effective strategies for disease prevention and treatment.
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Meeker, A.K. (2007). Telomeres, Telomerase, Chromosome Stability, and Prostate Cancer. In: Chung, L.W.K., Isaacs, W.B., Simons, J.W. (eds) Prostate Cancer. Contemporary Cancer Research. Humana Press. https://doi.org/10.1007/978-1-59745-224-3_18
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