Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Telomerase therapeutics for cancer: challenges and new directions

Nature Reviews Drug Discovery volume 5, pages 577–584 (2006)Cite this article

Key Points

  • Telomeres are the linear ends of chromosomes and are important in completing DNA replication. Telomeres and telomere-associated proteins cap the chromosome ends, preventing recombination, end-to-end fusions and degradation. Telomeres progressively shorten throughout life and most pre-cancerous lesions have very short telomeres.

  • Immortalization is required for most advanced human malignancies to continue to divide. The cellular reverse transcriptase telomerase is upregulated in almost all cancers and permits the indefinite growth of human cancer cells.

  • Approaches that specifically interfere with telomerase represent a novel targeted cancer therapy forcing cells back into a senescent or apoptotic pathway.

  • Clinical trials targeting telomerase include vaccines that recognize telomerase epitopes inappropriately expressed on tumour cells and small-molecule inhibitors such as a 13-mer oligonucleotide called GRN163L

  • Other approaches in preclinical studies include a telomerase-specific oncolytic virus that exclusively replicates in and lyses cells that actively express telomerase.

  • Most cancers are heterogeneous and contain cancer stem cells as well as more differentiated cancer cells. It is now known that telomerase is expressed in at least some types of cancer stem cells and that they contain short telomeres. Therefore, telomerase inhibitors could also target cancer stem cells.

Abstract

It has been approximately a decade since telomerase was described as an almost universal marker for human cancer. Most human tumours not only express telomerase but also have very short telomeres, whereas telomerase activity is either reduced or absent in normal tissues, making the inhibition of telomerase an attractive target for cancer therapeutics. Here we review the current status of telomerase therapeutics and discuss future opportunities and challenges for telomerase research, including a possible relationship with cancer stem cells that could be a source of chemo-/radioresistance development in many advanced cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Telomerase components.
Figure 2: Comparing telomerase inhibition in normal versus cancer cells.
Figure 3: Predicted outcomes of telomerase therapy.

Similar content being viewed by others

References

  1. Moyzis, R. K. et al. A highly conserved repetitive DNA sequence (TTAGGG)n, present at the telomeres of human chromosomes. Proc. Natl Acad. Sci. USA 85, 6622–6626 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Blackburn, E. H. Telomere states and cell fates. Nature 408, 53–56 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. de Lange, T. Protection of mammalian telomeres. Oncogene 21, 532–540 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999). Provides the first direct evidence that telomeres form a duplex loop instead of ending in a linear fashion.

    Article  CAS  PubMed  Google Scholar 

  5. Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Wright, W. E., Pereira-Smith, O. M. & Shay, J. W. Reversible cellular senescence: a two-stage model for the immortalization of normal human diploid fibroblasts. Mol. Cell. Biol. 9, 3088–3092 (1989). The first report defining two stages of cellular senescence in human cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995). Reports the initial cloning of hTR, the functional or template RNA subunit of human telomerase.

    Article  CAS  PubMed  Google Scholar 

  8. Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and humans. Science 277, 955–959 (1997). Reports the initial cloning of hTERT, the catalytic subunit of human telomerase.

    Article  CAS  PubMed  Google Scholar 

  9. Lingner, J. & Cech, T. R. Telomerase and chromosome end maintenance. Curr. Opin. Genet. Dev. 8, 226–232 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Collins, K. & Mitchell, J. R. Telomerase in the human organism. Oncogene 21, 564–579 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Nugent, C. I. & Lundblad, V. The telomerase reverse transcriptase: components and regulation. Genes. Dev. 12, 1073–1085 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–117 (1996). The first report to demonstrate telomerase activity in human germline and embryonic tissues, and its repression during development.

    Article  CAS  PubMed  Google Scholar 

  13. Aisner, D. L., Wright, W. E. & Shay, J. W. Telomerase regulation: not just flipping the switch. Curr. Opin. Genet. Dev. 12, 80–85 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Forsyth, N. R, Wright. W. E. & Shay, J. W. Telomerase and differentiation in multicellular organisms:Turn it off, turn it on, and turn it off again. Differentiation 69, 188–197 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). First report that the introduction of hTERT is sufficient to produce telomerase activity, maintain or elongate telomeres, and immortalize normal diploid human cells.

    Article  CAS  PubMed  Google Scholar 

  16. Shay, J. W. & Roninson, I. B. Hallmarks of senescence in carcinogenesis and cancer therapy Oncogene 23, 2919–2933 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Shay, J. W. & Wright, W. E. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 25, 1–8 (2004).

    Google Scholar 

  18. Shay, J. W. & Wright, W. E. Hayflick, his limit, and cellular ageing. Nature Rev. Mol. Cell Biol. 1, 72–76 (2000).

    Article  CAS  Google Scholar 

  19. Shay, J. W. & Wright, W. E. Telomeres in dyskeratosis congenita. Nature Genet. 36, 437–438 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985). First paper to identify the existence of telomerase activity approximately 10 years before the main components, TERT and TR, were cloned.

    Article  CAS  PubMed  Google Scholar 

  22. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994). First report to describe TRAP (PCR-based telomerase activity assay) and to demonstrate telomerase activity in a large panel of primary human cancers but not in normal human tissues.

    Article  CAS  PubMed  Google Scholar 

  23. Shay, J. W. & Bacchetti, S. A survey of telomerase activity in human cancer. Eur. J. Cancer 5, 787–791 (1997). Provides an overview of the diagnostic potential of measuring telomerase activity in human cancer.

    Article  Google Scholar 

  24. Shay, J. W. Telomerase in cancer: diagnostic, prognostic, and therapeutic implications. Cancer J. Sci. Am. (Suppl. 1), S26–S34 (1998).

  25. Hodes, R. Molecular targeting of cancer: telomeres as targets. Proc. Natl Acad. Sci. USA 98, 7649–7651 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saretzki, G. Telomerase inhibition as cancer therapy. Cancer Letter. 194, 209–219 (2003).

    Article  CAS  Google Scholar 

  27. Kelland, L. R. Telomerase: biology and phase I trials. Lancet Oncol. 2, 95–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. White, L. K., Wright, W. E. & Shay, J. W. Telomerase inhibitors. Trends Biotechnol. 19, 114–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Shay, J. W. & Wright, W. E. Mechanism-based combination telomerase inhibition therapy. Cancer Cell. 7, 1–2 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Neidle, S. & Parkinson, G. Telomere maintenance as a target for anticancer drug discovery. Nature Rev. Drug Discov. 1, 383–393 (2002).

    Article  CAS  Google Scholar 

  31. Helder, M. N., Wisman, G. B. A. & van der Zee, A. G. J. Telomerase and telomeres: from basic biology to cancer treatment. Cancer Invest. 20, 82–101 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Blasco, M. A. Telomeres and human disease: ageing, cancer and beyond. Nature Rev. Genet. 6, 611–622 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. McKenzie, K. E., Umbricht C. B. & Sukumar S. Applications of telomerase research in the fight against cancer. Mol. Med. Today 5, 114–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Shay, J. W. Meeting Report: The role of telomeres and telomerase in cancer. Cancer Res. 65, 3513–3517 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Gellert, G. C., Jackson, S. R. Dikmen, G., Wright, W. E. & Shay, J. W. Telomerase as a therapeutic target in cancer. Drug Discov. Today 2, 159–164 (2005).

    Article  CAS  Google Scholar 

  36. Shay, J. W. & Wright W. E. in Telomeres 2nd Edn (Eds. deLange, T., Lundblad, V. Blackburn, E.) 81–108 (Cold Spring Harbor Laboratory, New York, 2005).

    Google Scholar 

  37. Granger M. P., Wright W. E. & Shay J. W. Telomerase in cancer and aging. Crit. Rev. Oncol. Hematol. 4, 29–40 (2002).

    Article  Google Scholar 

  38. Shay, J. W. & Gazdar, A. F. Telomerase in the early detection of cancer. J. Clin. Pathol. 50, 106–109 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gilley, D., Tanaka, H. & Herbert, B.-S. Telomere dysfunction in aging and cancer. Intl J. Biochem. Cell Biol. 37, 1000–1013 (2005).

    Article  CAS  Google Scholar 

  40. Gowan, S. M. et al. A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 61, 1154–1162 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Read, M. A. et al. Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships. J. Med. Chem. 42, 4538–4546 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Riou, J. F. et al. Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc. Natl Acad. Sci. USA 99, 2672–2677 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, M. M. et al. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc. Natl Acad. Sci. USA 98, 7982–7987 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Minev, B. et al. Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc. Natl Acad. Sci. USA 97, 4796–4801 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nair, S. K. et al. Induction of cytotoxic T lymphocyte responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nature Med. 6, 1011–1017 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Vonderheide, R. H. et al. Vaccination of cancer patients against telomerase induces functional anti-tumor CD8+ T lymphocytes. Clin. Cancer Res. 10, 828–839 (2004). First intradermal immunotherapy trial directed against telomerase in patients with breast cancer resistant to conventional cytotoxic therapy or progressive hormone-independent prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  47. Vonderheide, R. H. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene 21, 674–679 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Brunsvig, P. F. et al. Telomerase peptide vaccination: a Phase I/II study in patients with non-small cell lung cancer. Cancer Immunol. Immunother. 21 Feb 2006 [epub ahead of print].

  49. Su, Z. et al. Telomerase mRNA-tranfected dendritic cells stimulate antigen-specific CD8+ and CD4+ cell responses in patients with metastatic prostate cancer. J. Immunol. 174, 3798–3807 (2005). First immunotherapy trial directed against telomerase (hTERT) mRNA-transfected dendritic cells in patients with metastatic prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  50. Chen, Z., Koeneman, K. S. & Corey, D. R. Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res. 63, 5917–5925 (2003).

    CAS  PubMed  Google Scholar 

  51. Gaudernack, G. et al. Clinical trials of a peptide vaccine targeting telomerase. ASCO Annu. Mtg A666 (2003).

  52. Corey, D. R. Telomerase: an unusual target for cytotoxic agents. Chem. Res. Toxicol. 13, 957–960 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Dikmen, Z. G. et al. In vivo inhibition of lung cancer by GRN163L — a novel human telomerase inhibitor. Cancer Res. 65, 7866–7873 (2005). First demonstration that the telomerase inhibitor GRN163L prevents lung metastasis in a xenograft animal model.

    Article  CAS  PubMed  Google Scholar 

  54. Gellert, G. C., Dikmen, Z. G., Wright, W. E., Gryaznov, S. & Shay, J. W. Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer. Breast Cancer Res. Treatment (in the press).

  55. Djojosubroto, M. W. et al. Telomerase antagonist GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. (in press, Hepatology, 2006)

  56. Gryaznov, S. et al. Telomerase inhibitors – oligonucleotide phosphoramidates as potential therapeutic agents. Nucleosides Nucleotides Nucleic Acids 20, 401–410 (2001).

    Google Scholar 

  57. Herbert, B.-S. et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA 96, 14276–14281 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Herbert, B-S., Pongracz, K. Shay, J. W. & Gryaznov, S. M. Oligonucleotide N3′-P5′ phosphoramidates as efficient telomerase inhibitors Oncogene 21, 638–642 (2002).

    Article  PubMed  Google Scholar 

  59. Asai, A. et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. 63, 3931–3939 (2003).

    CAS  PubMed  Google Scholar 

  60. Gu, J. et al. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers. Cancer Res. 60, 5359–5364 (2001).

    Google Scholar 

  61. Gu, J., Andreff, M., Roth, J. A. & Fang, B. hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity. Gene Ther. 9, 30–37 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Koga, S. et al. A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter. Hum. Gene Ther. 11, 1397–1406 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Koga, S. et al. FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo. Anticancer Res 21, 1937–1943 (2001).

    CAS  PubMed  Google Scholar 

  64. Komata, T. et al. Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter. Cancer Res. 61, 5796–5802 (2001).

    CAS  PubMed  Google Scholar 

  65. Majumdar, A. S. et al. The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters. Gene Ther. 8, 568–578 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Abdul-Ghani, R. et al. Use of transcriptional regulatory sequences of telomerase (hTER and hTERT) for selective killing of cancer cells. Mol. Ther. 2, 539–544 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Plumb, J. A. et al. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Oncogene 20, 7797–7803 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Bilsland, A. E., Fletcher-Monaghan, A. & Keith, W. N. Properties of a telomerase-specific cre/lox switch for transcriptionally targeted cancer gene therapy. Neoplasia 10, 1–10 (2006).

    Google Scholar 

  69. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Goodell, M. A. et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nature Med. 3, 1337–1345 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Wang, J. C. Y. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 1, 494–501 (2005).

    Article  CAS  Google Scholar 

  72. Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J. & Terzis, A. J. A. The origin of the cancer stem cells: current controversies and new insights. Nature Rev. Genet. 5, 899–904 (2005).

    Article  CAS  Google Scholar 

  73. Welm, B. E. et al. Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev. Biol. 245, 42–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Clayton, H., Titley, I. & Vivanco, M. Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp. Cell Res. 297, 444–460 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ponit, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005). First paper to demonstrate telomerase activity in cancer stem cells

    Article  Google Scholar 

  77. Campbell, L. J. et al. hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia. Leukemia 20, 671–679 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, J. C. Y. et al. Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc. Natl Acad. Sci. USA 102, 14398–14403 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shay, J. W., Pereira-Smith, O. M. & Wright, W. E. A role for both Rb and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta 1072, 1–7 (1991).

    CAS  PubMed  Google Scholar 

  81. Wright, W. E. & Shay, J. W. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr. Opin. Genet. Dev. 11, 98–103 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Zou, Y., Sfeir, A., Shay, J. W. & Wright, W. E. Does a sentinel or groups of short telomeres determine replicative senescence? Mol. Biol. Cell. 15, 3709–3718 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Goytisolo, F. A & Blasco, M. A. Many ways to telomere dysfunction: in vivo studies using mouse models. Oncogene 21, 584–591(2002).

    Article  CAS  PubMed  Google Scholar 

  84. Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis and cancer. Science 297, 565–569 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Feldser, D. M., Hackett, J. A. & Greider, C. W. Telomere dysfunction and the initiation of genome instability. Nature Rev. Cancer 3, 1–5 (2003).

    Article  CAS  Google Scholar 

  86. Dokal, I. & Vulliamy T. in Telomeres 2nd Edn (Eds. deLange, T., Lundblad, V. Blackburn, E.) 139–161 (Cold Spring Harbor Laboratory, New York, 2005).

    Google Scholar 

  87. Gomez, D. et al. Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing. Nucl. Acids Res. 31, 371–379 (2004).

    Article  Google Scholar 

  88. Cristofari, G. & Lingner, J. in Telomeres 2nd Edn (Eds. deLange, T., Lundblad, V. Blackburn, E.) 21–47 (Cold Spring Harbor Laboratory, New York, 2005).

    Google Scholar 

  89. Chen, J-L. & Greider, C. W. in Telomeres 2nd Edn (Eds. deLange, T., Lundblad, V. Blackburn, E.) 49–79 (Cold Spring Harbor Laboratory, New York, 2005).

    Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the Southland Foundation Distinguished Chair in Geriatrics Research, the Ellison Medical Foundation, and NSCOR and National Cancer Institute grants. We also acknowledge A. Diehl for providing drafts of the figures used in this review.

Author information

Authors and Affiliations

  1. Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9039, Texas, USA

    Jerry W. Shay & Woodring E. Wright

Authors
  1. Jerry W. Shay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Woodring E. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerry W. Shay.

Ethics declarations

Competing interests

Both authors are scientific advisory board members of the Geron Corp.

Related links

Related links

FURTHER INFORMATION

Shay/Wright Laboratory website

Glossary

Replicative senescence

The process by which most normal human cells 'count' the number of times they have divided, eventually undergoing an irreversible growth arrest due to telomere shortening on a few chromosome ends.

Mitotic catastrophe

A response to abnormal mitotic DNA damage, leading to cell death. Normal cells avoid mitotic catastrophe by activating different cell-cycle checkpoint genes, which allows cells to repair the damage before mitosis; this mechanism is absent in checkpoint-deficient cells with critically shortened telomeres.

Telomerase reverse transcriptase

(hTERT). The catalytic subunit of telomerase (an RNA-dependent DNA polymerase) that synthesizes telomeric repeats onto the end of telomeres using the integral RNA (hTR) component as a template.

Telomerase RNA

(hTR/hTERC). The integral RNA that provides an 11-bp template complementary to the telomeric repeats to be added to the chromosome.

Crisis

A balance between cell growth and cell death. When cells bypass replicative senescence, telomeres continue to shorten, eventually leading to mitotic catastrophe. These cells die or, rarely, reactivate telomerase, leading to an immortalized cell line.

Cancer stem cells

A small subset of tumour cells that can recreate and sustain (re-initiate, re-populate) the tumour in a functional transplant assay. It is believed that cancer stem cells have multilineage potential and might be responsible for the failure of current therapies.

Prostate-specific antigen

A serine protease in the kallikrein gene family that is secreted into seminal fluid by prostatic epithelial cells and found in the serum. As it is almost exclusively a product of prostate cells, measurement in blood has proved to be exceptionally useful as a tumour marker for diagnosis of prostate cancer and monitoring the effectiveness of treatment.

Xenograft

Transplantation of tissue or cells from one species to another. In cancer research, most xenografts are human cancer cell lines or human tumours that have been transplanted to immune-deficient rodents.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shay, J., Wright, W. Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov 5, 577–584 (2006). https://doi.org/10.1038/nrd2081

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2081

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing