Theodorescu, Dan

CU Scholar Institutional Repository

Platinum Priority – EditorialReferring to the articles published on pp. 360–366 and pp. 367–369 of this issueTelomerase in Bladder Cancer: Back to a Better Future?Dan Theodorescu a,b,*, Thomas R. Cech b,ca Department of Surgery, University of Colorado, Aurora, CO, USA; b University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; c Howard HughesMedical Institute, Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado, Boulder, CO, USAProper maintenance of chromosomes requires dealing withtwo biological challenges: the chromosome end-protectionproblem and the chromosome end-replication problem [1].The first challenge stems from the need to distinguish theends of linear chromosomes, which predominate ineukaryotes, from broken DNA ends that require repair.The second challenge stems from the gradual loss ofsequence information at the extreme end of chromosomes,owing to incomplete replication by DNA polymerases(which only synthesize DNA in the 50 to 30 direction andare unable to fill in the gap left behind upon removal of the50-most RNA primer). Telomerase, a unique enzyme thatcontains telomerase reverse transcriptase (TERT) and atemplate-containing RNA component (telomerase RNA[TR]), extends telomeric DNA to solve both problems.In mammals, the action of telomerase is required for thesurvival of continuously dividing cells such as embryoniccells and adult stem cells. These cells have relatively highlevels of telomerase activity, whereas most somatic cells,which have a limited replicative lifespan, have very low orundetectable telomerase activity. Inactivation of telome-rase in these latter cells is achieved mostly by transcrip-tional downregulation of the TERT gene, which encodesthe essential, catalytically active protein subunit of theenzyme [2]. TERT protein associates with the essentialTR subunit of the enzyme, which templates telomereextension, and with other protein factors to form the activeholoenzyme that maintains telomere length [1].TERT expression is also sometimes regulated by produc-tion of alternatively spliced messenger RNA (mRNA) variantsthat delete essential reverse transcriptase motifs of theenzyme. Increased abundance of these variants correlateswith inactivation of telomerase during tissue differentiation,whereas increased levels of mRNAs encoding full-lengthTERT occur in some lymphomas and activated T cells [3–6].Most cancer cells (85–90%) upregulate TERT protein toreactivate telomerase and maintain telomere lengthsthrough an indefinite number of cell divisions, and theremainder also maintain telomere length through analternative lengthening of telomeres mechanism.Recently, TERT promoter mutations have been found athigh frequency in many diverse cancers but not in adjacentnormal tissue [7,8]. An exciting breakthrough was findingpoint mutations in the TERT gene promoter in 66% ofurothelial carcinomas of the bladder [7,8]. These mutationswere first reported in melanoma [9,10] and quickly found inother cancers [7,8,10]. In contrast, only 1% of cancers havemutations in the TERT open reading frame [11], and eventhese have not been shown to be activating mutations,suggesting that telomerase reactivation is primarilyachieved through increased gene expression by transactingfactors. Although these promoter mutations were hypothe-sized to increase expression of TERT by generatingadditional binding sites for E-twenty-six (ETS) transcriptionfactors, only 1.15- to 2-fold increases in expression werefound using a luciferase reporter gene system [9,10,12].Additional mechanistic analysis is needed to determine ifsuch modest increases in TERT expression can indeed driveimmortalization or if the artificial reporter gene systemsgreatly underestimate the effect of the mutation; certainlyother possibilities exist as well.In this month’s issue of European Urology, two studies[13,14] follow up on these investigations and show thatmutation analysis of the TERT promoter allows bladdertumor cells to be detected in urine. In addition, these studiesshow that TERT promoter mutations are found at similarE U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 3 7 0 – 3 7 1avai lable at www.sciencedirect .comjournal homepage: www.europeanurology.comDOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2013.08.052, http://dx.doi.org/10.1016/j.eururo.2013.08.057.* Corresponding author. University of Colorado Cancer Center, Surgery, Cancer Research, 13001 E.17th Pl. MS #F-434, Aurora, CO 80045, USA.Tel. +1 303 724 7135; Fax: +1 303 724 3162.E-mail address: dan.theodorescu@ucdenver.edu (D. Theodorescu).0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.http://dx.doi.org/10.1016/j.eururo.2013.10.019frequency across tumor stage, and there is lack ofassociation with clinical outcome. These exciting studiesfurther reinvigorate recent interest in telomerase inurothelial carcinoma that began in the early 1990s. In1995, work indicated that in human urothelial carcinoma,telomere length was reduced in tumor tissue, more so innon–muscle-invasive than in invasive tumors, whereastelomerase was detectable only in tumor tissues and itsactivity was surprisingly unrelated to telomere length [15].Other early work reported that telomerase activity had anassociation with the pathologic grade and clinical stage,with most advanced grade and deeply invasive tumorshaving high telomerase activity [16]. Many subsequentstudies addressed whether telomerase could be used insome manner to detect bladder cancer [17], but noneprogressed to the clinical realm.Taken together, these recent findings answer somequestions and raise many others. It now appears that usingcurrent molecular technology, we can potentially detectapproximately two-thirds of bladder cancers by searchingfor TERT promoter mutations in the urine. The clinicalspecificity, sensitivity, and positive and negative predictivevalues determined in larger prospective studies will be keyin determining the value of any clinical test based on thisobservation. An important message also delivered by thesestudies is that TERT promoter mutations are not preferen-tially associated with either non–muscle-invasive or inva-sive bladder cancer and thus are likely to be a requirementfor transformation or maintenance of malignancy in mosturothelial tumors. Somewhat paradoxically, bladder can-cers have shorter telomeres than cognate normal urothe-lium [15], also raising a question about the impact of thesemutations. We do not yet understand the true biologicalcontribution of these mutations to the malignant pheno-type in urothelial carcinoma biology. Nevertheless, furtherwork on this gene, its regulation, and its clinical utility willbe very exciting, as it will likely lead to novel and practicalinsights into bladder cancer biology. In addition, we expectthat these findings will rekindle interest in telomerase as anattractive therapeutic target.Conflicts of interest: The authors have nothing to disclose.Funding support: This work was supported in part by HHMI (to T.R.C.)and CA143971 (to D.T.).References[1] Nandakumar J, Cech TR. Finding the end: recruitment of telomeraseto telomeres. Nat Rev Mol Cell Biol 2013;14:69–82.[2] Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR.Reverse transcriptase motifs in the catalytic subunit of telomerase.Science 1997;276:561–7.[3] Jalink M, Ge Z, Liu C, Bjorkholm M, Gruber A, Xu D. Human normal Tlymphocytes and lymphoid cell lines do express alternative splicingvariants of human telomerase reverse transcriptase (hTERT) mRNA.Biochem Biophys Res Commun 2007;353:999–1003.[4] Kilian A, Bowtell DD, Abud HE, et al. Isolation of a candidatehuman telomerase catalytic subunit gene, which reveals complexsplicing patterns in different cell types. Hum Mol Genet 1997;6:2011–9.[5] Liu K, Hodes RJ, Weng N. Cutting edge: telomerase activation inhuman T lymphocytes does not require increase in telomerasereverse transcriptase (hTERT) protein but is associated with hTERTphosphorylation and nuclear translocation. J Immunol 2001;166:4826–30.[6] Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR. Telomeraseactivity in human development is regulated by human telomerasereverse transcriptase (hTERT) transcription and by alternate splic-ing of hTERT transcripts. Cancer Res 1998;58:4168–72.[7] Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occurfrequently in gliomas and a subset of tumors derived from cellswith low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021–6.[8] Lotsch D, Ghanim B, Laaber M, et al. Prognostic significance oftelomerase-associated parameters in glioblastoma: effect of patientage. Neuro Oncol 2013;15:423–32.[9] Horn S, Figl A, Rachakonda PS, et al. TERT promoter mutations infamilial and sporadic melanoma. Science 2013;339:959–61.[10] Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highlyrecurrent TERT promoter mutations in human melanoma. Science2013;339:957–9.[11] The cancer genome atlas. National Institutes of Health Web site.http://cancergenome.nih.gov.[12] Xu D, Dwyer J, Li H, Duan W, Liu JP. Ets2 maintains hTERT geneexpression and breast cancer cell proliferation by interacting withc-Myc. J Biol Chem 2008;283:23567–80.[13] Allory Y, Beukers W, Sagrera A, et al. Telomerase reverse transcrip-tase promoter mutations in bladder cancer: high frequency acrossstages, detection in urine, and lack of association with outcome.Eur Urol 2014;65:360–6.[14] Hurst CD, Platt FM, Knowles MA. Comprehensive mutation analysisof the TERT promoter in bladder cancer and detection of mutationsin voided urine. Eur Urol 2014;65:367–9.[15] Kamata S, Kageyama Y, Yonese J, Oshima H. Significant telomerereduction in human superficial transitional cell carcinoma. Br J Urol1996;78:704–8.[16] Lin Y, Miyamoto H, Fujinami K, et al. Telomerase activity in humanbladder cancer. Clin Cancer Res 1996;2:929–32.[17] Dalbagni G, Han W, Zhang ZF, et al. Evaluation of the telomeric repeatamplification protocol (TRAP) assay for telomerase as a diagnosticmodality in recurrent bladder cancer. Clin Cancer Res 1997;3:1593–8.E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 3 7 0 – 3 7 1 371

Undetermined

Telomerase in Bladder Cancer: Back to a Better Future?

http://scholar.colorado.edu/cgi/viewcontent.cgi?article=1000&context=chem_facpapers

Telomerase in Bladder Cancer: Back to a Better Future?

Abstract

Similar works

Full text

Available Versions

CU Scholar Institutional Repository