TY - JOUR
T1 - Telomeres and telomerase in prostate cancer development and therapy
AU - Graham, Mindy Kim
AU - Meeker, Alan
N1 - Funding Information:
The authors wish to thank Dr Christopher Michael Heaphy and Dr Karen Sandell Sfanos for critical reading of the manu‑ script. 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.).
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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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U2 - 10.1038/nrurol.2017.104
DO - 10.1038/nrurol.2017.104
M3 - Review article
C2 - 28675175
AN - SCOPUS:85030540888
SN - 1759-4812
VL - 14
SP - 607
EP - 619
JO - Nature Reviews Urology
JF - Nature Reviews Urology
IS - 10
ER -