2022 Nov 28;13(11):1005. doi: 10.1038/s41419-022-05443-y. The telomerase RNA is built into the structure of the core ribonucleoprotein complex of telomerase, which contains the protein TERT and the telomerase RNA component. Herein, an enzyme-free electroanal. This is probably due to the all-encompassing anabolic effects of cellular growth caused by the main growth pathway in the body mTOR that will grow healthy cells but unfortunately sustains cancerous cells as well if they . Encouragingly, this is effective even with very low levels of expression of the mutant-template RNAs. Telomerase inhibitor BIBR1532 prevents Kras G12D -Calu-3 xenograft tumor growth and increases the, Figure 6. 2000;10:147154. We did these experiments in a manner that made the test of the effects as stringent as possible because we did not include a drug selection step after infecting the cells with the lentiviral vectors. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Another study from the same group further clarified this potential link between telomerase expression and myofibroblast differentiation (18); using the same bleomycin-induced pulmonary fibrosis rat model, they demonstrated that the inhibition of fibroblast telomerase activity led to increased -SMA expression, which represents a marker of . 2003 Nov-Dec;2(6):679-84. Which of the following statements is accurate about the activity of the telomerase enzyme in cancer cells? signals of methylene blue (MB) catalyzed by well monodisperse Au nanorods (AuNRs). In the context of the human body, the fact that the action of telomerase allows cells to keep multiplying can have different kinds of consequences. In contrast to the effects of mutant-template telomerase RNA expression on telomerase RNA knockdown, no telomere shortening or telomere uncapping, or DNA damage response, accompanied the cell growth rate decrease. Delayed effect: bulk telomeres decline to critical short length? Unable to load your collection due to an error, Unable to load your delegates due to an error, Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. Telomerase therapy has been shown to improve healthspan in mice and to increase survival in patients with cancer. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and Ferrara MG, Stefani A, Pilotto S, Carbone C, Vita E, Di Salvatore M, D'Argento E, Sparagna I, Monaca F, Valente G, Vitale A, Piro G, Belluomini L, Milella M, Tortora G, Bria E. Front Oncol. After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). Various lines of evidence showed that the cells that grew out were those that either did not receive the lentivector or failed to overexpress the mutant-template telomerase RNA. Thus, again, no evidence was found for any resistant subpopulation of cells that evade the effect of mutant-template telomerase RNA expression. Like an aglet, the telomere prevents that end from fraying away. In the current work, we investigated the relationship between genetically predicted LTL and lung . Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Telomerase and the benefits of healthy living. In collaboration with Mohammed Kashani-Sabet and his group at University of California, San Francisco, we examined the effect of telomerase RNA knockdown on metastasis in two in vivo models. Telomere terminal transferase (telomerase) enzyme activity (not the identification of the genes encoding the components of telomerase) was discovered in 1985 in the single-cell organism Tetrahymena ().Almost a decade later, telomerase was described as an almost universal marker in advanced human cancers (), but it was not until 1997 that the catalytic protein component was isolated, first in . Hence, the DNA at the ends of the chromosomes was effectively naked. HHS Vulnerability Disclosure, Help The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We were never able to obtain cells that stably expressed more than just a low fraction of the mutant-template kind of telomerase RNA. This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. The significance of telomerase activation and cellular immortalization in human cancer. An official website of the United States government. 24 patients had sufficient PBMCs needed for longitudinal analysis. In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. Given this nding and the pilot nature of this study, we report . 2022 Sep 16;10(9):2299. doi: 10.3390/biomedicines10092299. HHS Vulnerability Disclosure, Help Systematic review of the impact of a plant-based diet on prostate cancer incidence and outcomes. -, Calado RT, Young NS. Bookshelf Mol Cancer Res (2005) 3 (9): 477-482. Delay dependent on initial telomere length in the cancer cells? Hence, our attempts to intervene in telomerase action have led us unexpectedly down a new avenue in which we find telomerase doing things that we never expected to see. We mutated the telomerase RNA template so that now a mutated DNA sequence was added to the chromosomes, directed by the mutated template. Please enable it to take advantage of the complete set of features! Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. Reproduced from the Proceedings of the National Academy of Sciences, U.S.A., 2001;98:79827 by copyright permission of the National Academy of Sciences, U.S.A. (5). The unexpectedly rapid response to telomerase knockdown prompted us to carry out many controls to rule out possibilities such as targets other than the telomerase RNA being responsible for the effects on cell growth. In contrast, telomerase activity is silenced in most adult somatic cells. cancer cells employ . and transmitted securely. Researchers found that the enzyme telomerase, which is active in most tumor cells, may also protect healthy adult cells from becoming cancerous. MeSH 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. . which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. 3). -, Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. NCI CPTC Antibody Characterization Program, Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Telomere disease. Targeting. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). Valdiani A, Ofoghi H, Akbarizare M, Talei D. 3 Biotech. DNA Southern blot experiments, done to examine the length of the telomeric DNA, showed that there was no bulk shortening of the telomeres. Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Northern blot analysis of RNA extracted from a human cancer cell line, MCF-7. Hence, all one needed to do was spike the endogenous telomerase in the cancer cells with a little mutant-template telomerase RNA that assembled into the telomerase to make mutant repeats. 2009;6:201205. Bookshelf Thomas . sharing sensitive information, make sure youre on a federal PBMC telomerase activity in these men increased 29.84% within just 3 months of making significant . Similar findings were also made in the setting of a simple xenograft model: When we xenografted human cancer cells expressing the mutant-template telomerase RNA into a mouse model, we saw greatly decreased tumor growth and some regression of the tumors, accompanied by high rates of apoptosis in the tumors (5). Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Thus, the RNA and the protein of telomerase collaborate in the enzymatic action. scientists may be able to stop cancer progression and potentially increase mortality. R01 CA215733/CA/NCI NIH HHS/United States, P30 CA010815/CA/NCI NIH HHS/United States, P01 CA114046/CA/NCI NIH HHS/United States, R01 CA226888/CA/NCI NIH HHS/United States, R01CA215733/U.S. Cell aging in relation to stress arousal and cardiovascular disease risk factors. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). Although that experiment showed that with enough telomerase the telomeres can be maintained, the length at which they are maintained in a cell is the result of a complex interplay among many different factors. . Each ribozyme was delivered systemically after B16 cells had been introduced into mice by tail-vein injection. Bethesda, MD 20894, Web Policies Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. It has been postulated that the expression of the ribonucleoprotein telomerase is necessary to overcome cellular senescence and that malignant tumors must express telomerase to maintain their immortality. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Careers. Telomerase is an enzyme that can rebuild telomeres. Clin Cancer Res. Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres.A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes.Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. Telomeres and human disease: aging, cancer and beyond. PMC J. Mol. 1999;97:527538. Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. Reproduced from the Proceedings of the National Academy of Sciences, U.S.A., 2001;98:79827 by copyright permission of the National Academy of Sciences, U.S.A. (5). Kenessey I, Ki K, Horvth O, Cserepes M, Molnr D, Izsk V, Dobos J, Hegeds B, Tvri J, Tmr J. Oncotarget. Karadayi S, Arslan S, Sumer Z, Turan M, Sumer H, Karadayi K. Mol Biol Rep. 2013 Aug;40(8):4701-4. doi: 10.1007/s11033-013-2565-8. CA: A Cancer Journal for Clinicians. This study was published in the prestigious . Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. Psychoneuroendocrinology. Epub 2019 Aug 13. Diminished telomerase activity by MMPL resulted in the suppression of both telomerase . official website and that any information you provide is encrypted HHS Vulnerability Disclosure, Help Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. The results are the means SEM (n=3). 2009;361:23532365. KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. Epub 2020 Feb 27. Federal government websites often end in .gov or .mil. The fact that telomerase activity declines in somatic cells during adulthood, and that cell transformation and im-mortalization are often associated with increased telom-erase activity (Greider, 1998; Liu, 1999), suggests that telomerase has an antiaging function. 1998 Apr;102(4):397-402. doi: 10.1007/s004390050711. Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, . PMC 2006;26(1):91-6. doi: 10.1159/000092031. These proteins include DNA sequencespecific binding proteins and other proteins that together, in effect, sheathe the chromosome end. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. Therapies that increase telomerase activity can also slow the rate of telomere shortening. cancer cells employ . The chromosome ends become progressively shorter, which was predicted eventually to lead, by some unknown mechanism, to cells ceasing to divide. Curr Opin Hematol. Telomerase reactivation causes aggressive cancer Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. Instead, the affinity was increased by almost 3-fold as shown by the em K /em M values for the L-cysteine analog, RD-PNB (29 2.2 M) Mephenesin compared to the D-cysteine analog, L-70 (11 0.9 M). Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. 4). Mutat Res. Telomerase therapy is a promising approach to treating age-related diseases. official website and that any information you provide is encrypted Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. Interestingly, Zhang et al. This site needs JavaScript to work properly. Epub 2006 Mar 14. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. Keywords: using human cancer cells showed that TERT is a direct target of the Wnt/-catenin pathway and -catenin/TCF4 complex binds to the TERTp and increases telomerase activity Keshavarz M, Xie K, Schaaf K, Bano D, Ehninger D. Mol Psychiatry. Epub 2022 Aug 16. For these immunostaining experiments, we used proteins that are known to accumulate in DNA damage foci at sites of DNA damage, such as the protein hRif1. Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. Hum Genet. Cancer Ther 2 (2003): 209 -216. Genes Dev. Telomerase activity has been detected in 85% of tumors representing 15 cancer types, whereas most benign tumors and somatic tissues have very low levels or lack detectable telomerase activity Furthermore, in special metastatic tumor types such as neuroblastoma stage IVs, in which there is a high rate of spontaneous regression, telomerase . Clipboard, Search History, and several other advanced features are temporarily unavailable. However, blocking telomerase activity could affect cells where telomerase activity is . 2). Integrin V, which has been implicated in promoting tumor metastasis, was also suppressed. Mol Cancer Res 1 September 2005; 3 (9): 477482. Primarily, capping is accomplished through formation of a specific DNA-protein complex at the chromosomal terminus. Findings: The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). Clinically, metastasis is arguably the most important factor in cancer. Published in the November 2008 issue of Lancet Oncology, Dr. Dean Ornish's latest research, a pilot study on the effects of dietary and lifestyle changes in 30 men with low risk prostate cancer, suggests the answer is a resounding "Yes!". Telomerase Activity in Cancer - Telomerase usually active in normal stem cells but expressed in low or null levels in adult cells - Telomerase highly active in 85-95% of cancers (e., colonic adenocarcinoma) - Reactivation of telomerase allows tumour cells to escape apoptosis, causes genomic instability and accumulate further permanent mutations . Cell Chem Biol. -. Immunotherapies, MeSH The Chemopreventive Activity of Indonesia Medicinal Plants Targeting on Hallmarks of Cancer. Telomerase has been considered as a biomarker for early diagnosis and prognosis assessment of hepatocellular carcinoma (HCC), while the highly sensitive and specific methods remain challenging. Shang Li and Lifeng Xu showed that when we expressed the mutant-template telomerase RNA, even as early as 3 or 4 days after infection, DNA damage foci appeared at the telomeres, as visualized by immunostaining of the telomere-specific protein TRF2. 2011;23:149167. We expressed the telomerase RNA under a promoter that allowed telomerase to be expressed and active, even in cell lines that normally do not express any telomerase. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Thus, we converted an effectively immortal, perpetually growing organism into a mortal one by the simple action of making its telomerase nonfunctional, thereby showing that telomerase was important for the continued maintenance of the telomeres and of cell proliferation (3). Epub 2022 Jul 5. Cancer Epidemiol Biomarkers Prev. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. 2021 Jan 2;8(6):nwaa306. Nat Rev Cancer. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. As described above, the telomeric DNA sequence is specified by copying the telomerase RNA template. 2005;6:611622. Epub 2011 Jul 23. 2007;21(6):375-85. doi: 10.2165/00063030-200721060-00005. Epub 2005 Nov 17. In collaboration with Jerry Cunha's lab at University of California, San Francisco, human bladder tumor cells were xenografted under the renal capsule in a mouse. This site needs JavaScript to work properly. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047). Cancer Sci. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Through this work, we learned, somewhat to our surprise, that we might also be able to incur a more rapid effect on cancer cell growth than expected and even change their cancerous properties in ways that were hitherto unsuspected (7). Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. Increased telomerase activity in mouse skin premalignant progression. The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Telomerase activity analysis was . What this means at the molecular level is that the telomeric DNA contains binding sites for proteins that protect the end of the chromosome. Geron Corporation GERN, a late-stage clinical biopharmaceutical company, today highlighted multiple additions to its senior commercial leadership team, as it prepares for the potential . Epigenetics alternation in lung fibrosis and lung cancer. Previous studies have shown that injecting the telomerase gene into the immune cells (T cells) in our body can help keep the telomeres from getting shorter and enabling them to maintain their anti-viral functioning longer. 2015;65:87108. For example, we could reinfect those outgrowing cells and recapitulate the same growth kinetics compared with the controls for at least three cycles of reinfections. Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. As mentioned previously, if telomerase is present in sufficient amounts, it permits cells to keep multiplying. is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer. . Gene Dev. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. We used this organism because it has a large number of telomeres and is a relatively rich source of telomerase. Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. 5. FOIA After 30 days, the tumor burden in the lungs, representing metastatic tumors in the lungs, was quantified. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. Tornesello ML, Cerasuolo A, Starita N, Tornesello AL, Bonelli P, Tuccillo FM, Buonaguro L, Isaguliants MG, Buonaguro FM. A delay ensues, during which telomeres shorten, before the cells finally cease to grow. Lancet Oncol. Identification of a specific telomere terminal transferase activity in. The https:// ensures that you are connecting to the Semeraro MD, Almer G, Renner W, Gruber HJ, Herrmann M. Cells. A complex set of biological functions is encompassed in the word capping of the ends of the chromosomes. cancer cells employ . sharing sensitive information, make sure youre on a federal Maciejewska N, Olszewski M, Jurasz J, Baginski M, Stasevych M, Zvarych V, Folini M, Zaffaroni N. Cell Death Dis. This work comprises one approach by which one might exploit the increased expression of telomerase, which is so common in cancer cells by forcing them to make toxic telomeres. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. Polymorphisms in telomere maintenance genes and risk of lung cancer. As Bernard Weinstein (9) has proposed for other signaling pathways in tumors, cancer cells might be addicted to high levels of telomerase, such that their physiology becomes habituated to it that when telomerase is withdrawn, a cold turkey response is deleterious to the cell. Note: Although not eating fish is better for your telomeres, eating fish isn't necessarily bad for you. The https:// ensures that you are connecting to the -, Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, Nafa K, Riedel ER, Hsu M, Pao W, Miller VA, Ladanyi M. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Efficient platforms for detecting telomerase activity are essential for early tumor monitoring and diagnosis. PMC Federal government websites often end in .gov or .mil. The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. Even people living in the Blue Zones eat fish in moderation. Nuclear telomerase extracts were obtained from human breast cancer PMC42 cells transfected for 15 h with dierent hTERT cDNA expression constructs as indicated. Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years.. Several researchers in the area, along with "life extensionists", "immortalists" or "longevists" (those who wish to achieve longer lives themselves), postulate that future . Cell. . Epub 2022 Oct 10. https://doi.org/10.1158/1541-7786.MCR-05-0147. DNA methylation of the TERT promoter and its impact on human cancer. -, Morrison SJ, Prowse KR, Ho P, Weissman IL. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. Epub 2013 Sep 17. Epub 2019 Jun 1. it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. Mutagenesis. US11007255B2 - Cancer vaccines and methods of treatment using the same - Google Patents . 1994;266:20115. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). Wolkowitz OM, Mellon SH, Lindqvist D, Epel ES, Blackburn EH, Lin J, Reus VI, Burke H, Rosser R, Mahan L, Mackin S, Yang T, Weiner M, Mueller S. Psychiatry Res. 1). Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted Granger et al. Careers. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. The resulting structure is very dynamic. In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). The rapid response of telomerase-positive cancer cells to an abrupt depletion of their telomerase despite the lack of telomere uncapping prompted the hypothesis that these effects were unrelated to telomere maintenance or telomere function. False. Mol. The template is only a minor part of the entire telomerase RNA molecule. Epub 2012 Sep 10. We were able to show that this also occurs in vivo. In humans, gradual shortening of telomeres is observed throughout life in many cell types in every part of the body although the cells have a low level of telomerase. 3. Rapid down-regulation of genes promoting cell cycle progression and metastasis. Unable to load your collection due to an error, Unable to load your delegates due to an error. Epub 2022 Oct 6. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, P50 CA174523/CA/NCI NIH HHS/United States, P50CA174523/U.S. government site. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. Structural and Functional Changes in Aging Kidneys. The .gov means its official. The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. Clipboard, Search History, and several other advanced features are temporarily unavailable. eCollection 2021 Jan 19. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. Telomerase, the enzyme that reduces telomere shortening in certain cells, is reactivated or increased in more than 90 percent of cancers, found a 2016 study. Epub 2022 Jul 15. Curr Cancer Drug Targets. Please enable it to take advantage of the complete set of features! Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase. Our data strengthens the relationship of the Wnt/-catenin pathway and telomere length in the pathogenesis of aCPs. 8600 Rockville Pike Kras mutations upregulate TERT expression, Figure 1. . 2022 Oct 20;29(10):1517-1531.e7. Sunaga N, Kaira K, Imai H, Shimizu K, Nakano T, Shames DS, Girard L, Soh J, Sato M, Iwasaki Y, Ishizuka T, Gazdar AF, Minna JD, Mori M. Oncogene. Jacobs F, Cani M, Malapelle U, Novello S, Napoli VM, Bironzo P. Cancers (Basel). An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. Genetic Variants of the TERT Gene and Telomere Length in Obstructive Sleep Apnea. Direct telomerase inhibitors small molecules can bind to TERT and inhibit its catalytic activity resulting in gradual telomere attrition. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Exp Cell Res. Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova EV, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Jnne PA. Clin Cancer Res. Gupta N, Patel HD, Taylor J, Borin JF, Jacobsohn K, Kenfield SA, Eggener SE, Price C, Davuluri M, Byrne N, Bivalacqua TJ, Loeb S. Prostate Cancer Prostatic Dis. Introduction. . At a Glance. Would you like email updates of new search results? strategy was developed for reliable and highly sensitive telomerase activity assay based on the increased electrochem. However, development of telomerase inhibitors . Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Interestingly, despite being continually serially passaged for months, we never observed any reversion or any fast-growing resistant subpopulations growing out from 80 to 100 different clonal lines that were followed. The mutant-template telomerase RNA caused uncapping of the telomeres. Before . The site is secure. Epub 2015 Jan 19. 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. Yu GL, Bradley JD, Attardi LD, Blackburn EH. How do you increase telomerase? government site. The telomeres consist, first, of a DNA scaffold composed of a tract of very simple repeated DNA sequences. Telomerase inhibitor BIBR1532 inhibits Kras mutations-induced cell transformation and migration capability, Figure 4. One reason is that, as was predicted in the 1970s, the known mechanism of DNA polymerase prevents complete DNA replication all the way to the ends of the chromosome at every round of replication. Macek P, Poreba R, Gac P, Bogunia-Kubik K, Dratwa M, Wieckiewicz M, Wojakowska A, Michalek-Zrabkowska M, Mazur G, Martynowicz H. Biomedicines. PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). The pseudoknot is also critically important for the action of telomerase. Thus, incomplete replication of the chromosome ends occurs, which, if left unchecked by any compensatory mechanism, leads to a problem of maintaining the full-length of chromosomal DNA molecules. Once again, the effects did not require p53 (7). Alternatively, oligonucleotides complementary to the TERC template region can act as competitive telomerase inhibitors. PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. The first way of intervening in telomerase action in human cancer cells exploited the fact that the telomeric DNA makes the molecular scaffold for the binding of telomere-protective proteins, which include DNA sequencespecific binding proteins. They hypothesized that this region was key to regulating telomerase activity and began to experiment on melanoma cells. Bethesda, MD 20894, Web Policies The primary endpoint was telomerase enzymatic activity per viable cell, measured at . Careers. Increased telomerase activity was associated with a decrease in the level of low-density lipoprotein cholesterol (LDL) and a decrease . (4) showed in a sufficiency experiment that forced ectopic overexpression of telomerase is sufficient to overcome cellular senescence in culture and maintain the telomeres at a steady length as cells continue to divide. Bethesda, MD 20894, Web Policies We could achieve up to about 90% knockdown either by using short hairpin siRNAs expressed in the cells from a lentiviral vector expression cassette or by treating the cancer cells with the short synthetic siRNA oligonucleotides with or without modified backbones (Fig. Suspi- M.P. Supporting this model, Shang Li, in collaboration with Chris Haqq and his group at University of California, San Francisco, showed that global gene expression profile changed within 4 days after the telomerase RNA was knocked down. Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. That property also makes telomerase a very unusual reverse transcriptase. Remember, this enzyme isn't found in . Immunotherapies - Peptide or DNA vaccines supply immunogenic TERT epitopes that stimulate immune responses against telomerase-expressing cancer cells. The human telomerase RNA, a non-mRNA, can be efficiently knocked down by expression of a short hairpin RNA from a lentiviral construct. By continuing to use our website, you are agreeing to, Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture, Cancer Epidemiology, Biomarkers & Prevention, A Brief Review of Telomeres and Telomerase, Intervening in the Action of Telomerase in Human Cancer Cells, Forcing Telomerase to Make Mutant Telomeric DNA in Cancer Cells, Unexpected Short-term Effects of Knocking Down Telomerase Activity in Cancer Cells, https://doi.org/10.1158/1541-7786.MCR-05-0147, The Prostate Stromal Transcriptome in Aggressive and Lethal Prostate Cancer, IFT20 Confers Paclitaxel Resistance by Triggering -arrestin-1 to Modulate ASK1 Signaling in Breast Cancer, Malignant Progression of an Ancestral Bone Marrow Clone Harboring a, Improved Delineation of Colorectal Cancer Molecular Subtypes and Functional Profiles with a 62-Gene Panel, Cancer Epidemiology, Biomarkers, & Prevention. -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. When compared with the parent cell line, in which the p53 locus is left intact, the responses between the lines were similar. Thus, although telomerase is growth-regulated in tissues and cell types that express it, there may be some . doi: 10.1016/j.chembiol.2022.09.002. 2006 Apr;31(3):277-87. doi: 10.1016/j.psyneuen.2005.08.011. In contrast, telomerase activity is silenced in most adult somatic cells. 8600 Rockville Pike He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. Methods: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. Telomerase activity is decreased in peripheral blood mononuclear cells of hemodialysis patients. PubMed. It is this addition of telomeric DNA in increments to the ends of chromosomes that offsets and counterbalances the shortening of chromosome ends. We did something somewhat different: We knocked down the telomerase RNA levels so that now, not only was there less telomerase enzymatic activity but also the cell was depleted of telomerase ribonucleoprotein itself. Telomere length and the risk of lung cancer. The telomerase RNA of mouse melanoma cells (B16 cells) was targeted using ribozymes, and the human telomerase RNA in human melanoma cells was targeted using the siRNA approach described previously (8). Clearly, our challenge is to understand how such a mechanism might work. Telomerase as a therapeutic target in glioblastoma. A. Mutirangura, P. Supiyaphun, +4 . GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. The response to mutant-template telomerase RNA is highly specific for cells that have high levels of telomerase. Indeed, that expected result is exactly what is seen when the telomerase activity in cells is inhibited by, for example, expressing an excess of a catalytically dead version of the protein TERT, which, although it can still assemble into the telomerase ribonucleoprotein complex, forms a complex that is not catalytically active. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a significantly increased risk of lung cancer compared to subjects with high telomerase activity (adjusted odds ratio = 3.05, 95% confidence interval = 1.60-5.82, P = 7 10(-4)). The protein component of telomerase, telomerase reverse transcriptase (TERT), is indeed a protein enzyme and its amino acid sequence includes reverse transcriptase motifs. Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats. Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The problem was that previously, the only stable lines that grew out were those that had expressed extremely low levels of mutant-template telomerase RNA. Epub 2013 May 5. 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. We used a particular cell line, the LOX human melanoma cell line, which happens to have particularly long telomeres, about 40 kb. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. FOIA eCollection 2021 Jun. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. An update. Am J Hum Biol. -, Eisenberg DT. This site needs JavaScript to work properly. But there are risks. To detect telomerase, a novel surface-enhanced Raman scattering (SERS) biosensor was constructed using the dual DNA-catalyzed amplification strategy composed of strand displacement amplification (SDA . Bethesda, MD 20894, Web Policies Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Weinstein IB. Curr Opin Genet Dev. The expression of telomerase in various human cancers and its diminished expression in most normal cells suggest that the enzyme might serve as a good target for anticancer drugs. Epub 2018 Aug 2. 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. Progressing next generation of telomere-targeting candidates through proof of concept studies with promising anti-cancer activity Filed provisional new composition of matter patent during fourth . We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. Cell. Adv Pharm Bull. Cell Senescence Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Federal government websites often end in .gov or .mil. Epub 2022 Jul 5. Although the mouse telomerase RNA component levels were increased 2-fold and correlated well with proliferation markers, activity levels were increased 10-fold, suggesting a second level of regulation in addition to growth regulation . Armando R, Cabrera M, Vilarullo R, Chinestrad P, Maggio J, Paderta C, Lorenzano Menna P, Gomez D, Mengual Gmez D. Oncol Rep. 2022 Nov;48(5):188. doi: 10.3892/or.2022.8403. Figure 1. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. Bodnar AG, Ouellette M, Frolkis M, et al. An official website of the United States government. 8600 Rockville Pike And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. Resulting in the overall . 2003 Oct 1;289(2):326-34. doi: 10.1016/s0014-4827(03)00281-7. Telomere end-replication problem and cell aging. Tieing together loose ends: telomere instability in cancer and aging. [The 2009 Nobel Prize in Medicine and its surprising message: lifestyle is associated with telomerase activity]. In 1998, Bodnar et al. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Telomeres, telomerase, and myc. Telomerase is commonly expressed in human cancer cells. We were originally able to show that if we interfered with the action of telomerase in this organism, the telomeres gradually became shorter and cells eventually ceased to divide. 2015 Apr 30;232(1):58-64. doi: 10.1016/j.pscychresns.2015.01.007. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Methods: Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. government site. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH Ovals and diamonds, sequence-specific DNA binding proteins that protect telomeric DNA and cap it; red, telomerase; blue Xs, mutated telomerase RNA template and correspondingly mutated telomeric DNA sequence. The core structure includes a conserved pseudoknot, which is one of the parts of RNA that interact tightly and specifically with the protein TERT in the enzyme complex. FOIA While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. government site. This site uses cookies. Inhibition of telomerase activity leads to a very simple expectation: Failure to counteract telomere shortening, the result of incomplete DNA replication, would cause the telomeres to get shorter and shorter and eventually they would become too short to sustain capping, and some signaling process would direct the cells to cease multiplying or even undergo apoptosis. Front Cell Dev Biol. 2022 Oct 26;14(21):5257. doi: 10.3390/cancers14215257. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . See this image and copyright information in PMC. official website and that any information you provide is encrypted Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. Unable to load your collection due to an error, Unable to load your delegates due to an error. The .gov means its official. Recent studies also suggest that telomerase is implicated in tumor . Would you like email updates of new search results? The regulation of telomerase activity in human cells plays a significant role in the development of cancer. . Choi JE, Kang HG, Jang JS, Choi YY, Kim MJ, Kim JS, Jeon HS, Lee WK, Cha SI, Kim CH, Kam S, Jung TH, Park JY. HHS Vulnerability Disclosure, Help While telomerase activity is detected in cells with high proliferation potential, in somatic cells it is virtually undetected resulting in the overall shortening of telomeres with each cell division. This inactive complex swamps out the endogenous telomerase. One line of evidence for the lack of p53 protein requirement came from the use of a p53-null human colon cancer cell line kindly provided by Dr. Burt Vogelstein. Li S, Rosenberg JE, Donjacour AA, et al. 8600 Rockville Pike Published in Cancer Research 1996. Also, Ground flax and chia seeds are excellent vegan sources of short-chain (ALA) omega-3s. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Would you like email updates of new search results? While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. Extension of life span by introduction of telomerase into normal human cells. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. 1999;97:50314. Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. G-quadruplex (G4) stabilizers disrupt telomerase function by blocking the resolution of telomeric G-quadruplex DNA. Would you like email updates of new search results? doi: 10.1093/nsr/nwaa306. -cancer cells show decreased telomerase activity and the telomeres are shortened. Drugs that inhibit telomerase activity, or kill telomerase-producing cells, may potentially stop and kill cancer cells in their tracks. Elizabeth H. Blackburn; Telomerase and Cancer: Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. levels of TERT or telomerase activity (Fu et al., 2000). 2019 Nov 15;105(4):861-874. doi: 10.1016/j.ijrobp.2019.08.009. These observations lead us to investigate the most efficient means of inhibiting telomerase in cancer cells. At various levels, it is also active in other adult human cells, but the levels are often very low and not enough to sustain telomere length over a lifetime. 2. BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. Xu L, Blackburn EH. Telomerase is silenced in most normal cells but is active in an estimated 85% to 95% of human cancer cells. Increase Telomerase and Telomeres Naturally. It is in that latter context that we are interested in intervening in telomerase action. An increase in telomerase activity in one context could be viewed as beneficial because it might lead to an increase in relative telomere length . Telomerase levels are very highly regulated in normal human cells. -, Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. The solution to this theoretical problem was the enzyme telomerase (1). High telomerase . Please enable it to take advantage of the complete set of features! Cancers (Basel). Disclaimer, National Library of Medicine The number of papillomas showing higher levels of telomerase activity increased at 20 weeks, and at 30 weeks of promotion, 100% of papillomas expressed significantly higher levels of telomerase. Such cell death is, in effect, a one-way streetonce they make the decision to enter apoptosis, the cells cannot recover to generate any further daughter cells. The effects were different from the gene expression effects elicited by mutant-template telomerase RNA expression (7). Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. Keywords: 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. The authors declare that they have no conflict of interest. Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. Recent work has confirmed these observations in both solid and hematopoietic cancers (5), leading to the proposal that telomerase expression may prove to be an important diagnostic tool as well as a novel target for cancer therapy. These cancer cells already had high levels of telomerase, including high levels of the normal wild-type telomerase RNA. We interpret these findings to mean that as the cells grew, with some probability they would die by apoptosis. Authors have no potential conflicts of interest to disclose. Within a few days, the cell growth rate was markedly decreased. Nat Rev Genet. Cold Spring Harbor Lab; 2005;19:210010. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. The telomere, after all, represents a DNA end, which is at the end of the linear chromosomal DNA, but it has to be treated in a different way from an accidental DNA break in a chromosome. The .gov means its official. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. An example of mutated bases in the telomerase RNA and complementary mutant DNA bases incorporated into telomeric DNA (red A's and T's, respectively) through copying of the mutant telomerase template. An official website of the United States government. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). Hence, the telomeric structure is continually being assembled and disassembled. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Cancer Biol Ther. eCollection 2021. Lin J, Ly H, Hussain A, et al. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. We were, however, unable to rule out the possibility that telomerase activation over such a short time was a compensatory mechanism induced by adverse conditions (eg, a worsening of prostate cancer). Use of the D- in place of L-cysteine did not prevent hydrolysis by PMPMEase. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. This increased expression of telomerase makes it an attractive target for intervention. We observed that at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of telomerase activity. Disclaimer, National Library of Medicine Kras mutations; chemoresistance; lung cancer; telomerase; telomere. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. -cancer . "Inhibition of Telomerase activity in human cancer cells by RNA interference". . Telomerase was found to be highly expressed in dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer in rats, and its high activity was associated with increased TERT expression. . 2021 Dec 16;13(24):6332. doi: 10.3390/cancers13246332. Finally, we observed the same kinds of rapid growth inhibitory effects in the context of a more in vivolike setting for tumor cells. / Critical Re6iews in Oncology/Hematology 41 (2002) 29-40 37 cious cytogenetic abnormalities in breast cancer corre- with telomerase activity were ultimately diagnosed as late with increased telomerase activity, namely 3q+ carcinoma and 6/7 without telomerase activity were (site of hTR), 8q+ (c-myc), and 17p (p53 . Telomere shortening is counteracted by the cellular enzyme telomerase. We therefore investigated what happens when you knock down the high levels of telomerase in human cancer cells. The ribozyme treatment decreased the metastatic burden. Larger randomised controlled trials are warranted to confirm the findings of this study. Epub 2009 Sep 22. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Tumor cells in control . CHICAGO--(BUSINESS WIRE)-- MAIA Biotechnology, Inc. (NYSE American: MAIA) announced today the advancement of its Telomere-Targeting Molecule Program ("Project T3").MAIA is designing and evaluating multiple telomere-targeting compounds designed to modify the telomeric structure through the cancer cell - intrinsic telomerase activity - and thus cause the death of these cells. Accessibility Specific association of human telomerase activity with immortal cells and cancer. 2022 Sep;25(3):444-452. doi: 10.1038/s41391-022-00553-2. 2008;14:57315734. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. MEK inhibition led to reduced TERT expression and telomerase activity. Too much telomerase can help confer immortality onto cancer cells and actually increase the likelihood of cancer, . Search for other works by this author on: Greider CW, Blackburn EH. As a result, cancer cells essentially become immortal. Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. One of the telomerase-specific oncolytic adenovirus . Cancer research, 1995. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Thomas Slaga . Immunity. 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