Ovarian Cancer pp 213-228 | Cite as

Telomerase and Malignant Transformation

  • Jiamei Yu
  • Louis Dubeau
Part of the Cancer Treatment and Research book series (CTAR, volume 107)


Recent progress in our understanding of the role of telomeres and telomerase in cell proliferation, malignant transformation, and genomic stability has opened new possibilities for cancer diagnosis, detection, and treatment. Novel approaches based on this knowledge are being investigated in different laboratories and are likely to have a significant impact on cancer management protocols in the future. This chapter gives an overview of our current knowledge of the function of telomeres and of the mechanisms responsible for their maintenance, followed by comments on potential applications of this knowledge in clinical medicine.


Telomere Length hTERT Expression Telomere Elongation 
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  1. (1).
    Blackburn EH: Structure and function of telomeres. Nature 1991; 350: 569–573.PubMedCrossRefGoogle Scholar
  2. (2).
    Levis RW, Ganesan R, Houtchens K, et al: Transposons in place of telomeric repeats at a Drosophila telomere. Cell 1993; 75: 1083–1093.PubMedCrossRefGoogle Scholar
  3. (3).
    Shampay J, Szostak JW, Blackburn EH: Cloning yeast telomeres on linear plasmid vectors. Cell 1982; 29: 245–255.CrossRefGoogle Scholar
  4. Greider CW, Blackburn EH: The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 1987; 51: 887–898.CrossRefGoogle Scholar
  5. Greider CW, Blackburn EH: A telomeric sequence in the RNA of Tetrahymena telomerase required for telomerase repeat synthesis. Nature 1989; 337: 331–337.CrossRefGoogle Scholar
  6. (6).
    Greider CW: Mammalian telomere dynamics: healing, fragmentation shortening and stabilization. Curr. Opinion Genet. Dev. 1994; 4: 203–211.CrossRefGoogle Scholar
  7. (7).
    Olovnikov AM: A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 1973; 41: 181–190.PubMedCrossRefGoogle Scholar
  8. (8).
    Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345: 458–460.PubMedCrossRefGoogle Scholar
  9. (9).
    Allsopp RC, Vaziri H, Patterson C, et al: Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl. Acad. Sci. 1992; 89: 10114–10118.PubMedCrossRefGoogle Scholar
  10. (10).
    Kim NW, Piatyszek MA, Prowse KR, et al: Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2015.PubMedCrossRefGoogle Scholar
  11. (11).
    Hanahan D, Weinberg RA, 2000: The hallmarks of cancer. Cell 2000; 100: 57–70.CrossRefGoogle Scholar
  12. (12).
    Meyerson M, Counter CM, Eaton EN, et al: hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90: 785–795.PubMedCrossRefGoogle Scholar
  13. (13).
    Harrington L, McPhail T, Mar V, et al: A mammalian telomerase-associated protein. Science 1997; 275: 973–977.PubMedCrossRefGoogle Scholar
  14. (14).
    Nakayama J, Saito M, Nakamura H, et al: TLP1: a gene encoding a protein component of mammalian telomerase-associated protein. Science 1997; 275: 973–977.CrossRefGoogle Scholar
  15. (15).
    Gilley D, Blackburn EH: The telomerase RNA pseudoknot is critical for the stable assembly of a catalytically active ribonucleoprotein. Proc. Natl. Acad. Sci. 1999; 96: 6621–6625.PubMedCrossRefGoogle Scholar
  16. (16).
    Chen JL, Blasco MA, Greider CW: Secondary structure of vertebrate telomerase RNA. Cell 2000; 5: 503–514.CrossRefGoogle Scholar
  17. (17).
    Tesmer VM, Ford LP, Holt SE, et al: Two inactive fragments of the integral RNA cooperate to assemble active telomerase with the human protein catalytic subunit (hTERT) in vitro. Molec. Cell. Biol. 1999; 19: 6207–6216.Google Scholar
  18. (18).
    Le S, Stemglanz R, Greider CW: Identification of two RNA-binding proteins associated with human telomerase RNA. Molec. Biol. Cell 2000; 11: 999–1010.PubMedGoogle Scholar
  19. (19).
    Holt SE, Aisner DL, Baur J, et al: Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 1999; 13: 817–826.PubMedCrossRefGoogle Scholar
  20. (20).
    Nakayama J, Tahara H, Tahara E, et al: Telomerase activation by hTRT in human nomial fibroblasts and hepatocellular carcinomas. Nature Genet. 1998; 18: 65–68.PubMedCrossRefGoogle Scholar
  21. (21).
    Ramakrishnan S, Eppenberger U, Mueller H, et al: Expression profile of the putative catalytic subunit of the telomerase gene. Cancer Res. 1998; 58: 622–625.PubMedGoogle Scholar
  22. (22).
    Kilian A, Bowtell DD, Abud HE, et al: Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum. Molec. Genet. 1997; 6:2011–2019,.Google Scholar
  23. (23).
    Tommerup H, Dousmanis A, de Lange T: Unusual chromatin in human telomeres. Mol. Cell. Biol. 1994; 14: 5777–5785.PubMedCrossRefGoogle Scholar
  24. (24).
    Griffith JD, Comeau L, Rosenfield S, et al: Mammalian telomeres end in a large duplex loop. Cell 1999; 97: 503–514.PubMedCrossRefGoogle Scholar
  25. (25).
    Chong L, van Steensel B, Broccoli D, et al: A human telomeric protein. Science 1995; 270: 1663–1667.PubMedCrossRefGoogle Scholar
  26. (26).
    Shen M, Haggblom C, Vogt M, et al: Characterization and cell cycle regulation of the related human telomeric proteins Pin2 and TRF1 suggest a role in mitosis. Proc. Natl. Acad. Sci. 1997; 94: 13618–13623.PubMedCrossRefGoogle Scholar
  27. (27).
    Conrad MN, Wright JH, Wolf AJ, et al: RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomerestructure anddecreases chromosome stability. Cell 1990; 63: 739–750.PubMedCrossRefGoogle Scholar
  28. (28).
    Kyrion G, Boakye KA, Lustig Al C-terminal truncation of RAP1 results in the deregulation of telomere size, stability, and function in Saccharomyces cerevisiae. Molec. Cell. Biol. 1992; 12: 5159–5173.PubMedGoogle Scholar
  29. (29).
    van Steensel B, de Lange T: Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385: 740–743.PubMedCrossRefGoogle Scholar
  30. (30).
    Griffith J, Bianchi A, de Lange T: TRF1 promotes parallel pairing of telomeric tracts in vitro. J. Molec. Biol. 1998; 278: 79–88.PubMedCrossRefGoogle Scholar
  31. (31).
    Kim SH, Kaminker P, Campisi J: TIN2, a new regulator of telomere length in human cells. Nature Genet. 1999; 23: 405–412.PubMedCrossRefGoogle Scholar
  32. (32).
    van Steensel B, Smogorzewska A, de Lange T: TRF2 protects human telomeres from endto-end fusions. Cell 1998; 92: 401–413.PubMedCrossRefGoogle Scholar
  33. (33).
    Smith S, de Lange T: Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes. J. Cell Sci. 1999; 112: 3649–3656.PubMedGoogle Scholar
  34. (34).
    Smith S, Giriat I, Schmitt A, et al: Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 1998; 282: 1484–1487.PubMedCrossRefGoogle Scholar
  35. (35).
    Broccoli D, Young JW, de Lange T: Telomerase activity in normal and malignant hematopoietic cells. Proc. Natl. Acad. Sci. 1995; 92: 9082–9086.PubMedCrossRefGoogle Scholar
  36. (36).
    Hiyama K, Hirai Y, Kyoizumi S, et al: Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J. Immunol. 1995; 155: 3711–3715.PubMedGoogle Scholar
  37. (37).
    Yokoyama Y, Takahashi Y, Shinohara A, et al: Telomerase activity in the female reproductive tract and neoplasms. Gynecol. Oncol. 1998; 68: 145–149.PubMedCrossRefGoogle Scholar
  38. (38).
    Yokoyama Y, Takahashi Y, Morishita S, et al: Telomerase activity in the human endometrium throughout the menstrual cycle. Molec. Hum. Reprod. 1998; 4: 173–177.PubMedCrossRefGoogle Scholar
  39. (39).
    Tanaka M, Kyo S, Takakura M, et al: Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation. Am. J. Pathol. 1998; 153: 1985–1991.PubMedCrossRefGoogle Scholar
  40. (40).
    Nakamura Y, Tahara E, Tahara H, et al: Quantitative reevaluation oftelomerase activity in cancerous and noncancerous gastrointestinal tissues. Molec. Carcinog. 1999; 26: 312–320.CrossRefGoogle Scholar
  41. (41).
    Kolquist KA, Ellisen LW, Counter CM, et al: Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nature Genet. 1998; 19: 182–186.PubMedCrossRefGoogle Scholar
  42. (42).
    Le S, Moore JK, Haber JE, et al: RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics 1999; 152: 143–152.PubMedGoogle Scholar
  43. (43).
    Bryan T, Marusic L, Bacchetti S, et al: The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Hum. Molec. Genet. 1997; 6: 921–926.PubMedCrossRefGoogle Scholar
  44. (44).
    Rudolph KL, Chang S, Lee HW, et al: Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96: 701–712.PubMedCrossRefGoogle Scholar
  45. (45).
    Herbert B, Pitts AE, Baker SI, et al: Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl. Acad. Sci. 1999; 96: 14276–14281.PubMedCrossRefGoogle Scholar
  46. (46).
    Hahn WC, Stewart SA, Brooks MW, et al: Inhibition of telomerase limits the growth of human cancer cells. Nature Med. 1999; 5: 1164–1170.PubMedCrossRefGoogle Scholar
  47. (47).
    Murakami J, Nagai N, Shigemasa K, et al: Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines. Eur. J. Cancer 1999; 35: 1027–1034.PubMedCrossRefGoogle Scholar
  48. (48).
    Tendian SW, Parker WB: Interaction of deoxyguanosine nucleotide analogs with human telomerase. Mol. Phamracol. 2000; 57: 695–699.Google Scholar
  49. (49).
    Xu D, Umber A, Bjorkholm M, et al: Suppression of telomerase reverse transcriptase (hTERT) expression in differentiated HL-60 cells: regulatory mechanisms. Br. J. Cancer 1999; 80: 1156–1161.PubMedCrossRefGoogle Scholar
  50. (50).
    Horikawa I, Cable PL, Afshari C, et al: Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 1999; 59: 826–830.PubMedGoogle Scholar
  51. (51).
    Takakura M, Kyo S, Kanaya T, et al: Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999; 59: 55 1557.Google Scholar
  52. (52).
    Wick M, Zubov D, Hagen G: Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT). Gene 1999; 232: 97106.CrossRefGoogle Scholar
  53. (53).
    Cong YS, Wen J, Bacchetti S: The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum. Mo.l Genet. 1999; 8: 137–142.CrossRefGoogle Scholar
  54. (54).
    Greenberg RA, O’Hagan RC, Deng H, et al: Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 1999; 18: 1219–1226.PubMedCrossRefGoogle Scholar
  55. (55).
    Wu KJ, Grandori C, Amacker M, et al: Direct activation of TERT transcription by c-MYC. Nature Genet. 1999; 21: 220–224.PubMedCrossRefGoogle Scholar
  56. (56).
    Wang J, Xie LY, Allan S, et al: Myc activates telomerase. Genes Dev. 1998; 12:1769– 1774.Google Scholar
  57. (57).
    Kyo S, Takakura M, Taira T, et al: Sp 1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res. 2000; 28: 669–677.PubMedCrossRefGoogle Scholar
  58. (58).
    Oh S, Song YH, Yim J, et al: Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene 2000; 19: 1485–1490.PubMedCrossRefGoogle Scholar
  59. (59).
    Dessain SK, Yu H, Reddel RR, et al: Methylation of the human telomerase gene CpG island. Cancer Res. 2000; 60: 537–541.PubMedGoogle Scholar
  60. (60).
    Devereux TR, Horikawa I, Anna CH, et al: DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 1999; 59: 6087–6090.PubMedGoogle Scholar
  61. (61).
    Aldous WK, Marean AJ, DeHart MT, et al: Effects of tamoxifen on telomerase activity in breast carcinoma cell lines. Cancer 1999; 85: 1523–1529.PubMedCrossRefGoogle Scholar
  62. (62).
    Kyo S, Takakura M, Kanaya T, et al: Estrogen activates telomerase. Cancer Res. 1999; 59: 5917–5921.Google Scholar
  63. (63).
    Seimiya H, Tanji M, Oh-hara T, et al: Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells. Biochem. Biophy.s Res. Commun. 1999; 260: 365–370.Google Scholar
  64. (64).
    Sawa H, Kamada H, Ohshima TA, et al: Exogenous expression of p16INK4a is associated with decrease in telomerase activity. J. Neurooncol. 1999; 42: 45–57.PubMedCrossRefGoogle Scholar
  65. (65).
    Kusumoto M, Ogawa T, Mizumoto K, et al: Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 1999; 5: 2140–2147.PubMedGoogle Scholar
  66. (66).
    Li H, Cao Y, Berndt MC, et al: Molecular interactions between telomerase and the tumor suppressor protein p53in vitro. Oncogene 1999; 18: 6785–6794.PubMedCrossRefGoogle Scholar
  67. (67).
    Cuthbert AP, Bond J, Trott DA, et al: Telomerase repressor sequences on chromosome 3 and induction of pemlanent growth arrest in human breast cancer cells. J. Natl. Cancer Inst. 1999; 91: 37–45.PubMedCrossRefGoogle Scholar
  68. (68).
    Cheng PC, Gosewehr JA, Kim TM, et al: Potential role of the inactivated X chromosome in ovarian epithelial tumor development. J. Natl. Cancer Inst. 1996; 88: 510–518.PubMedCrossRefGoogle Scholar
  69. (69).
    Cliby W, Ritland S, Hartmann L, et al: Human epithelial ovarian cancer allelotype. Cancer Res. 1996; 53: 2393–2398.Google Scholar
  70. (70).
    Li H, Zhao L, Yang Z, et al: Telomerase is controlled by protein kinase Calpha in human breast cancer cells. J. Biol. Chem. 1998; 273: 33436–33442.PubMedCrossRefGoogle Scholar
  71. (71).
    Kong SS, Kwon T, Kwon DY, et al: Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J. Biol. Chem 1999; 274: 13085–13090.CrossRefGoogle Scholar
  72. (72).
    Uehara H, Nakaizumi A, Tatsuta M, et al: Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am. J. Gastroenterol. 1999; 94: 2513–2518.PubMedCrossRefGoogle Scholar
  73. (73).
    Yeh TS, Cheng AJ, Chen TC, et al: Telomerase activity is a useful marker to distinguish malignant pancreatic cystic tumors from benign neoplasms and pseudocysts. J. Surg. Res. 1999; 87: 171–177.PubMedCrossRefGoogle Scholar
  74. (74).
    Zeiger MA, Smallridge RC, Clark DP, et al: Human telomerase reverse transcriptase (hTERT) gene expression in FNA samples from thyroid neoplasms. Surgery 1999; 126: 1195–1199.PubMedCrossRefGoogle Scholar
  75. (75).
    Duggan B, Wan M, Yu M, et al: Detection of ovarian cancer cells: Comparison of a telomerase assay and cytologic examination. J. Natl. Cancer Inst. 1998; 90: 238–242.PubMedCrossRefGoogle Scholar
  76. (76).
    Toshima S, Arai T, Yasuda Y, et al: Cytological diagnosis and telomerase activity of cells in effusions of body cavities. Oncol. Res. 1999; 6: 199–203.Google Scholar
  77. (77).
    Tangkijvanich P, Tresukosol D, Sampatanukul P, et al: Telomerase assay for differentiating between malignancy-related and nonmalignant ascites. Clin. Cancer Res. 1999; 5: 2470–2475.PubMedGoogle Scholar
  78. (78).
    Pearson AS, Gollahon LS, O’Neal NC, etal: Detection of telomerase activityin breast masses by fine-needle aspiration. Ann. Surg. Oncol. 1998; 5: 186–193.PubMedCrossRefGoogle Scholar
  79. (79).
    Shroyer KR, Thompson LC, Enomoto T, et al: Telomerase expression in normal epithelium, reactive atypia, squamous dysplasia, and squamous cell carcinoma of the uterine cervix. Am. J. Clin. Pathol. 1998; 109: 153–162.PubMedGoogle Scholar
  80. (80).
    Snijders PJ, van Duin M, Walboomers JM, et al: Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA. Cancer Res. 1998; 58: 3812–3818.PubMedGoogle Scholar
  81. (81).
    Nakano K, Watney E, McDougall JK: Telomerase activity and expression of telomerase RNA component and telomerase catalytic subunit gene in cervical cancer. Am. J. Pathol. 1998; 153:857.-864.Google Scholar
  82. (82).
    Dome JS, Chung S, Bergemann T, et al: High telomerase reverse transcriptase (ITEM) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms’ tumor. Cancer Res. 1999; 59: 4301–4307.PubMedGoogle Scholar
  83. (83).
    Poremba C, Willenbring H, Hero B, et al: Telomerase activity distinguishes between neuroblastomas with good and poor prognosis. Ann. Oncol. 1999; 10: 715–721.PubMedCrossRefGoogle Scholar
  84. (84).
    Ramakumar S, Bhuiyan J, Besse JA, et al: Comparison of screening methods in the detection of bladder cancer. J. Urol. 1999; 161: 388–394.PubMedCrossRefGoogle Scholar
  85. (85).
    Muderspach L, Muggia FM, Conti PS: Second-look laparotomy for stage III epithelial ovarian cancer rationale and current issues. Cancer Treatment Rev. 1996; 21: 499–511.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Jiamei Yu
    • 1
  • Louis Dubeau
    • 1
  1. 1.Department of Pathology, Keck School of Medicine of the University of Southern CaliforniaUSC/Norris Comprehensive Cancer CenterLos AngelesUSA

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