Seminar article
Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology

https://doi.org/10.1016/j.urolonc.2005.11.002Get rights and content

Abstract

Telomeres are terminal, repeated deoxyribonucleic acid (DNA) sequences that stabilize and protect the ends of the chromosomes. Mounting evidence indicates that by initiating chromosomal instability, short dysfunctional telomeres may be involved in prostate carcinogenesis. Although the exact cause of the telomere shortening observed in prostate cancer remains a mystery, telomere loss is known to occur during cell division and oxidative DNA damage, 2 byproducts of chronic inflammation, which is a common histologic finding in the prostate. In addition to prostate cancer causation, telomeres may also play a role in disease progression, and there are indications that tumor telomere content may prove useful as a prognostic marker.

Once established, prostate cancer cells almost invariably activate the telomeric DNA polymerase enzyme telomerase, the detection of which may prove useful for diagnostic purposes. Interestingly, telomerase activity is suppressed in prostate cancer cells after androgen withdrawal, raising the possibility that androgen ablative therapies may re-instigate telomere loss, and consequent genetic instability, in surviving cancer cells, thus contributing to the emergence of an androgen-independent, lethal phenotype. A more thorough understanding of telomere biology as it relates to prostate cancer should provide new opportunities for disease prevention, diagnosis, prognostication, and treatment.

Introduction

Despite decades of research, we still lack a satisfactory understanding of prostate cancer causation and the factors that determine the clinical course of the disease. Prostate adenocarcinomas display notable morphologic and behavioral heterogeneities [1], [2], [3]. Unlike several other carcinomas in which 1 or a few key oncogenes or tumor suppressor genes are commonly found genetically or epigenetically altered, no such predominant alterations have been identified in prostate cancer [4], [5], [6], [7], [8]. Instead, published reports detail a host of diverse changes, including both losses and gains of genetic material throughout the genome [3], [9], [10], [11], [12], [13], [14], [15], [16]. It is reasonable to conclude that the marked phenotypic heterogeneity distinguishing prostate cancer is, in large part, a reflection of this underlying genetic heterogeneity. Telomere dysfunction can initiate genetic instability and has recently been found to occur early in the process of prostate carcinogenesis. This article will review the important role that telomeres may be playing in prostate cancer.

Section snippets

Telomeres and genetic instability in cancer

Two broad classes of genetic instability have been defined in human cancers: microsatellite instability (MIN) and chromosomal instability [17]. Microsatellite instability has been traced to defects in deoxyribonucleic acid (DNA) mismatch repair that result in an increased mutation frequency. However, evidence to date indicates that this pathway does not play a major role in the development of prostate cancer. On the other hand, chromosomal instability is a universal feature of prostate cancer

Telomerase in prostate cancer

In prostate cancer, telomerase activity has been detected in 47% to 100% of prostate cancers, with most studies showing activity in the majority of cases [54], [57], [58], [59], [60], [61], [62], [63], [64], [65]. These findings are in keeping with reports that prostate adenocarcinomas have shorter than normal telomeres, thus, telomerase activity is presumably required to allow continued tumor proliferation [58], [61]. In sharp contrast, activity is infrequently found in adjacent normal

Telomerase regulation

Known transcriptional regulators of hTERT include the positive regulators c-Myc and the polycomb protein CBX7, as well as the negatively acting regulators menin, Rak, SIP1, and the c-Myc antagonist Mad1 [102]. c-Myc is of interest in that its mRNA is reportedly increased in prostate cancer, it is correlated with a worse prognosis, and it is a candidate gene in a region of chromosome 8p, often found to be amplified in prostate cancer [103]. It is noteworthy that Latil et al. [79] found hTERT

Conclusions

Telomere shortening can initiate chromosomal instability and occurs early during prostate tumorigenesis. Therefore, it is a likely candidate for the source of the complex genetic changes underlying the phenotypic diversity of prostate cancer. If true, this helps resolve the puzzle of why prostate cancers appear to lack prevalent genetic changes in specific tumor suppressors, oncogenes, or genome stability genes. Instead, the source of chromosomal instability may stem from defects in fundamental

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