Cancer Letters
Volume 194, Issue 2 , Pages 163-172 , 15 May 2003

Telomerase and tumorigenesis

  • Kenkichi Masutomi

      Affiliations

    • Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Dana 710C, Boston, MA 02115, USA
    • Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
    • ,
  • William C. Hahn

      Affiliations

    • Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Dana 710C, Boston, MA 02115, USA
    • Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1-617-632-2641; fax: +1-617-632-2375

Received 29 August 2002 ,Revised 20 October 2002 ,Accepted 21 October 2002.

References 

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  2. Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat. Rev. Cancer. 2002;2:331–341
  3. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer [see comments]. Science. 1994;266:2011–2015
  4. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. Nature. 1999;400:464–468
  5. Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 2001;15:50–65
  6. Rich JN, Guo C, McLendon RE, Bigner DD, Wang XF, Counter CM. A genetically tractable model of human glioma formation. Cancer Res. 2001;61:3556–3560
  7. DePinho RA. The age of cancer. Nature. 2000;408:248–254
  8. Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106:661–673
  9. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–460
  10. Greider CW. Telomerase and telomere-length regulation: lessons from small eukaryotes to mammals. Cold Spring Harb. Symp. Quant. Biol. 1993;58:719–723
  11. Harley CB, Kim NW, Prowse KR, Weinrich SL, Hirsch KS, West MD, et al. Telomerase, cell immortality, and cancer. Cold Spring Harb. Symp. Quant. Biol. 1994;59:307–315
  12. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, et al. The RNA component of human telomerase. Science. 1995;269:1236–1241
  13. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. Reverse transcriptase motifs in the catalytic subunit of telomerase [see comments]. Science. 1997;276:561–567
  14. Nugent CI, Lundblad V. The telomerase reverse transcriptase: components and regulation. Genes Dev. 1998;12:1073–1085
  15. Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, et al. A mammalian telomerase-associated protein. Science. 1997;275:973–977
  16. Nakayama J, Saito M, Nakamura H, Matsuura A, Ishikawa F. TLP1: a gene encoding a protein component of mammalian telomerase is a novel member of WD repeats family. Cell. 1997;88:875–884
  17. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 1999;13:817–826
  18. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature. 2001;413:432–435
  19. Masutomi K, Kaneko S, Hayashi N, Yamashita T, Shirota Y, Kobayashi K, et al. Telomerase activity reconstituted in vitro with purified human telomerase reverse transcriptase and human telomerase RNA component. J. Biol. Chem. 2000;275:22568–22573
  20. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 1997;17:498–502
  21. Beattie TL, Zhou W, Robinson MO, Harrington L. Reconstitution of human telomerase activity in vitro. Curr. Biol. 1998;8:177–180
  22. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur. J. Cancer. 1997;33:787–791
  23. Hayflick L. Mortality and immortality at the cellular level. A review. Biochemistry (Moscow). 1997;62:1180–1190
  24. Wright WE, Shay JW. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 1992;27:383–389
  25. Newbold RF, Overell RW. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature. 1983;304:648–651
  26. Newbold RF, Overell RW, Connell JR. Induction of immortality is an early event in malignant transformation of mammalian cells by carcinogens. Nature. 1982;299:633–635
  27. Sager R. Senescence as a mode of tumor suppression. Environ. Health Perspect. 1991;93:59–62
  28. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, et al. Inhibition of telomerase limits the growth of human cancer cells. Nat. Med. 1999;5:1164–1170
  29. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 1999;13:2388–2399
  30. Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH, et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell. 1999;97:515–525
  31. Hackett JA, Greider CW. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene. 2002;21:619–626
  32. Wright WE, Shay JW. Historical claims and current interpretations of replicative aging. Nat. Biotechnol. 2002;20:682–688
  33. Shay JW, Wright WE. Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen. Exp. Cell Res. 1989;184:109–118
  34. Bond JA, Haughton MF, Rowson JM, Smith PJ, Gire V, Wynford-Thomas D, et al. Control of replicative life span in human cells: barriers to clonal expansion intermediate between M1 senescence and M2 crisis. Mol. Cell Biol. 1999;19:3103–3114
  35. Bright RK, Vocke CD, Emmert-Buck MR, Duray PH, Solomon D, Fetsch P, et al. Generation and genetic characterization of immortal human prostate epithelial cell lines derived from primary cancer specimens. Cancer Res. 1997;57:995–1002
  36. Wei W, Sedivy JM. Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures. Exp. Cell Res. 1999;253:519–522
  37. Harley CB, Vaziri H, Counter CM, Allsopp RC. The telomere hypothesis of cellular aging. Exp. Gerontol. 1992;27:375–382
  38. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science. 2002;295:2446–2449
  39. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, et al. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev. 2000;14:2807–2812
  40. Samper E, Goytisolo FA, Slijepcevic P, van Buul PP, Blasco MA. Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 2000;1:244–252
  41. Counter CM, Botelho FM, Wang P, Harley CB, Bacchetti S. Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein–Barr virus-transformed human B lymphocytes. J. Virol. 1994;68:3410–3414
  42. Klingelhutz AJ, Barber SA, Smith PP, Dyer K, McDougall JK. Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells. Mol. Cell Biol. 1994;14:961–969
  43. Stoppler H, Hartmann DP, Sherman L, Schlegel R. The human papillomavirus type 16 E6 and E7 oncoproteins dissociate cellular telomerase activity from the maintenance of telomere length. J. Biol. Chem. 1997;272:13332–13337
  44. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406:641–645
  45. Artandi SE, DePinho RA. Mice without telomerase: what can they teach us about human cancer?. Nat. Med. 2000;6:852–855
  46. Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–538
  47. van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92:401–413
  48. Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 1992;11:1921–1929
  49. Macera-Bloch L, Houghton J, Lenahan M, Jha KK, Ozer HL. Termination of lifespan of SV40-transformed human fibroblasts in crisis is due to apoptosis. J. Cell Physiol. 2002;190:332–344
  50. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells [see comments]. Science. 1998;279:349–352
  51. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998;396:84–88
  52. Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl. Acad. Sci. USA. 1998;95:14723–14728
  53. Halvorsen TL, Leibowitz G, Levine F. Telomerase activity is sufficient to allow transformed cells to escape from crisis. Mol. Cell Biol. 1999;19:1864–1870
  54. Zhu J, Wang H, Bishop JM, Blackburn EH. Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening [see comments]. Proc. Natl. Acad. Sci. USA. 1999;96:3723–3728
  55. Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983;304:596–602
  56. Ruley HE. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983;304:602–606
  57. Sager R, Tanaka K, Lau CC, Ebina Y, Anisowicz A. Resistance of human cells to tumorigenesis induced by cloned transforming genes. Proc. Natl. Acad. Sci. USA. 1983;80:7601–7605
  58. Wright WE, Shay JW. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat. Med. 2000;6:849–851
  59. Kipling D. Telomere structure and telomerase expression during mouse development and tumorigenesis. Eur. J. Cancer. 1997;33:792–800
  60. Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature. 1990;347:400–402
  61. Prowse KR, Greider CW. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl. Acad. Sci. USA. 1995;92:4818–4822
  62. Martin-Rivera L, Herrera E, Albar JP, Blasco MA. Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc. Natl. Acad. Sci. USA. 1998;95:10471–10476
  63. Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock?. Cell. 2000;102:407–410
  64. Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, et al. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol. Cell Biol. 2002;22:2111–2123
  65. Yu J, Boyapati A, Rundell K. Critical role for SV40 small-t antigen in human cell transformation. Virology. 2001;290:192–198
  66. Lundberg AS, Randell SH, Stewart SA, Elenbaas B, Hartwell KA, Brooks MW, et al. Immortalization and transformation of primary human airway epithelial cells by gene transfer. Oncogene. 2002;21:4577–4586
  67. MacKenzie KL, Franco S, Naiyer AJ, May C, Sadelain M, Rafii S, et al. Multiple stages of malignant transformation of human endothelial cells modelled by co-expression of telomerase reverse transcriptase, SV40 T antigen and oncogenic N-ras. Oncogene. 2002;21:4200–4211
  68. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91:25–34
  69. Gonzalez-Suarez E, Samper E, Flores JM, Blasco MA. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat. Genet. 2000;26:114–117
  70. Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat. Med. 1997;3:1271–1274
  71. Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR. The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Hum. Mol. Genet. 1997;6:921–926
  72. O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell. 2002;2:149–155
  73. Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 2001;28:155–159
  74. Smogorzewska A, De Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002;21:4338–4348
  75. Morales CP, Holt SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS, et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat. Genet. 1999;21:115–118
  76. Jiang XR, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, et al. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat. Genet. 1999;21:111–114
  77. Yatabe N, Kyo S, Kondo S, Kanaya T, Wang Z, Maida Y, et al. 2–5 A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells. Cancer Gene Ther. 2002;9:624–630
  78. Feng RH, Zhu ZG, Li JF, Liu BY, Yan M, Yin HR, et al. Inhibition of human telomerase in MKN-45 cell line by antisense hTR expression vector induces cell apoptosis and growth arrest. World J. Gastroenterol. 2002;8:436–440
  79. Herbert B, Pitts AE, Baker SI, Hamilton SE, Wright WE, Shay JW, et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl. Acad. Sci. USA. 1999;96:14276–14281
  80. Fletcher TM, Cathers BE, Ravikumar KS, Mamiya BM, Kerwin SM. Inhibition of human telomerase by 7-deaza-2′-deoxyguanosine nucleoside triphosphate analogs: potent inhibition by 6-thio-7-deaza-2′-deoxyguanosine 5′-triphosphate. Bioorg. Chem. 2001;29:36–55
  81. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001;20:6958–6968
  82. Herbert BS, Pongracz K, Shay JW, Gryaznov SM, Shea-Herbert B. Oligonucleotide N3′→P5′ phosphoramidates as efficient telomerase inhibitors. Oncogene. 2002;21:638–642
  83. Pruzan R, Pongracz K, Gietzen K, Wallweber G, Gryaznov S. Allosteric inhibitors of telomerase: oligonucleotide N3′→P5′ phosphoramidates. Nucleic Acids Res. 2002;30:559–568
  84. Gowan SM, Harrison JR, Patterson L, Valenti M, Read MA, Neidle S, et al. A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 2002;61:1154–1162
  85. Kim MY, Vankayalapati H, Shin-Ya K, Wierzba K, Hurley LH. Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex. J. Am. Chem. Soc. 2002;124:2098–2099
  86. Murakami C, Takemura M, Sugiyama Y, Kamisuki S, Asahara H, Kawasaki M, et al. Vitamin A-related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases. Biochim. Biophys. Acta. 2002;1574:85–92
  87. Pascolo E, Wenz C, Lingner J, Hauel N, Priepke H, Kauffmann I, et al. Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J. Biol. Chem. 2002;277:15566–15572
  88. Zaffaroni N, Lualdi S, Villa R, Bellarosa D, Cermele C, Felicetti P, et al. Inhibition of telomerase activity by a distamycin derivative: effects on cell proliferation and induction of apoptosis in human cancer cells. Eur. J. Cancer. 2002;38:1792
  89. Ludwig A, Saretzki G, Holm PS, Tiemann F, Lorenz M, Emrich T, et al. Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res. 2001;61:3053–3061
  90. Saretzki G, Ludwig A, von Zglinicki T, Runnebaum IB. Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells. Cancer Gene Ther. 2001;8:827–834
  91. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc. Natl. Acad. Sci. USA. 2001;98:7982–7987
  92. Gonzalez-Suarez E, Samper E, Ramirez A, Flores JM, Martin-Caballero J, Jorcano JL, et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 2001;20:2619–2630
  93. Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. USA. 2002;99:8191–8196
  94. Stewart SA, Hahn WC, O'Connor BF, Banner EN, Lundberg AS, Modha P, et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl. Acad. Sci. USA. 2002;99:12606–12611
  95. Blasco MA, Rizen M, Greider CW, Hanahan D. Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis. Nat. Genet. 1996;12:200–204
  96. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, et al. Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res. 2002;62:3876–3882
  97. Gorbunova V, Seluanov A, Pereira-Smith OM. Expression of hTERT does not prevent stress-induced senescence in normal human fibroblasts, but protects the cells from stress-induced apoptosis and necrosis. J. Biol. Chem. 2002;24:24
  98. Forsythe HL, Elmore LW, Jensen KO, Landon MR, Holt SE. Retroviral-mediated expression of telomerase in normal human cells provides a selective growth advantage. Int. J. Oncol. 2002;20:1137–1143
  99. Falchetti A, Becherini L, Martineti V, Morelli A, Benvenuti S, Picariello L, et al. Telomerase repeat amplification protocol (TRAP): a new molecular marker for parathyroid carcinoma. Biochem. Biophys. Res. Commun. 1999;265:252–255
  100. Hiyama E, Hiyama K. Clinical utility of telomerase in cancer. Oncogene. 2002;21:643–649
  101. Lancelin F, Anidjar M, Villette JM, Soliman A, Teillac P, Le Duc A, et al. Telomerase activity as a potential marker in preneoplastic bladder lesions. BJU Int. 2000;85:526–531
  102. Langford LA, Piatyszek MA, Xu R, Schold SC, Wright WE, Shay JW. Telomerase activity in ordinary meningiomas predicts poor outcome. Hum. Pathol. 1997;28:416–420
  103. Pearson AS, Chiao P, Zhang L, Zhang W, Larry L, Katz RL, et al. The detection of telomerase activity in patients with adenocarcinoma of the pancreas by fine needle aspiration. Int. J. Oncol. 2000;17:381–385
  104. Wisman GB, Knol AJ, Helder MN, Krans M, de Vries EG, Hollema H, et al. Telomerase in relation to clinicopathologic prognostic factors and survival in cervical cancer. Int. J. Cancer. 2001;91:658–664
  105. Matthews P, Jones CJ, Skinner J, Haughton M, de Micco C, Wynford-Thomas D. Telomerase activity and telomere length in thyroid neoplasia: biological and clinical implications. J. Pathol. 2001;194:183–193
  106. Koyanagi Y, Kobayashi D, Yajima T, Asanuma K, Kimura T, Sato T, et al. Telomerase activity is down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC during the differentiation of leukemic cells. Anticancer Res. 2000;20:773–778
  107. Hiyama E, Gollahon L, Kataoka T, Kuroi K, Yokoyama T, Gazdar AF, et al. Telomerase activity in human breast tumors. J. Natl. Cancer Inst. 1996;88:116–122
  108. Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, et al. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat. Genet. 1998;19:182–186
  109. Fang DC, Young J, Luo YH, Lu R, Jass J. Detection of telomerase activity in biopsy samples of colorectal cancer. J. Gastroenterol. Hepatol. 1999;14:328–332
  110. Vonderheide RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene. 2002;21:674–679
  111. Seger YR, Garcia-Gao M, Piccinin S, Cunsolo CL, Doglioni C, Blasco MA, et al. Transformation of normal human cells in the abscence of telomerase activation. Cancer Cell. 2002;2:401–413

PII: S0304-3835(02)00703-6

doi: 10.1016/S0304-3835(02)00703-6

Cancer Letters
Volume 194, Issue 2 , Pages 163-172 , 15 May 2003

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