Skip to main content
SpringerLink
Log in

Telomere Shortening and Telomerase Activation during Cancer Formation

  • Chapter
Telomeres and Telomerase in Ageing, Disease, and Cancer

  • 1371 Accesses

Telomere shortening limits the proliferative capacity of human cells by inducing cell cycle arrest/senescence or apoptosis. Telomere shortening and the activation of these checkpoints represent tumor suppressor mechanisms in humans. In contrast, telomere shortening can induce chromosomal instability during ageing and chronic disease. This correlates with an increased cancer risk. This chapter summarizes experimental data from mouse models as well as data from primary human cancer demonstrating that telomere shortening and telomerase activation have ambiguous functions in cancer formation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alonso MM, Fueyo J, Yung WK, Gomez-Manzano C (2006) E2F1 and telomerase: alliance in the dark side. Cell Cycle 5: 930–35.

    PubMed  CAS  Google Scholar 

  • Armanios M, Greider CW (2005) Telomerase and cancer stem cells. Cold Spring Harb Symp Quant Biol. 70: 205–08.

    Article  PubMed  CAS  Google Scholar 

  • Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406: 641–45.

    Article  PubMed  CAS  Google Scholar 

  • Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ 2nd, Wynshaw-Boris A, Levine RL (1999) Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA 96(17): 9915–19.

    Article  PubMed  CAS  Google Scholar 

  • Bellon M, Datta A, Brown M, Pouliquen JF, Couppie P, Kazanji M, Nicot C (2006) Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia. Int J Cancer 119: 2090–97.

    Article  PubMed  CAS  Google Scholar 

  • Bilousova G, Marusyk A, Porter CC, Cardiff RD, DeGregori J (2005) Impaired DNA replication within progenitor cell pools promotes leukemogenesis. PLOS Biol 3: e401.

    Article  PubMed  CAS  Google Scholar 

  • Blanco R, Munoz P, Flores JM, Klatt P, Blasco MA (2007) Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev 21: 206–20.

    Article  PubMed  CAS  Google Scholar 

  • Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34.

    Article  PubMed  CAS  Google Scholar 

  • Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831–34.

    Article  PubMed  CAS  Google Scholar 

  • Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97: 527–38.

    Article  PubMed  CAS  Google Scholar 

  • Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, Kuo WL, Ljung BM, Chew K, Myambo K, Miranda M, Krig S, Garbe J, Stampfer M, Yaswen P, Gray JW, Lockett SJ (2004) In situ analyses of genome instability in breast cancer. Nat Genet. 36: 984–88.

    Article  PubMed  CAS  Google Scholar 

  • Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39: 99–105.

    Article  PubMed  CAS  Google Scholar 

  • Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells–perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66: 9339–44.

    Article  PubMed  CAS  Google Scholar 

  • Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S (2007) Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep 8(5): 497–503.

    Article  PubMed  CAS  Google Scholar 

  • Cristofari G, Lingner J (2006) Telomere length homeostasis requires that telomerase levels are limiting. EMBO J 25: 565–74.

    Article  PubMed  CAS  Google Scholar 

  • d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194–98.

    Article  PubMed  CAS  Google Scholar 

  • de Lange T (2004) T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5: 323–29.

    Article  PubMed  CAS  Google Scholar 

  • Djojosubroto MW, Choi YS, Lee HW, Rudolph KL (2003) Telomeres and telomerase in ageing, regeneration and cancer. Mol Cells 15(2): 164–75.

    PubMed  CAS  Google Scholar 

  • Emerald BS, Chen Y, Zhu T, Zhu Z, Lee KO, Gluckman PD, Lobie PE (2007) AlphaCP1 mediates stabilization of hTERT mRNA by autocrine human growth hormone. J Biol Chem 282: 680–90.

    Article  PubMed  CAS  Google Scholar 

  • Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL, DePinho RA (2003) Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res 63(16): 5021–27.

    PubMed  CAS  Google Scholar 

  • Flores I, Evan G, Blasco MA (2006) Genetic analysis of myc and telomerase interactions in vivo. Mol Cell Biol 26: 6130–38.

    Article  PubMed  CAS  Google Scholar 

  • Gire V, Wynford-Thomas D (1998) Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol Cell Biol 18(3): 1611–21.

    PubMed  CAS  Google Scholar 

  • Gonzalez-Suarez E, Samper E, Flores JM, Blasco MA (2000) Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 26: 114–17.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH, Greider CW, DePinho RA (1999a) Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97: 515–25.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg RA, O’Hagan RC, Deng H, Xiao Q, Hann SR, Adams RR, Lichtsteiner S, Chin L, Morin GB, DePinho RA (1999b) Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18: 1219–26.

    Article  PubMed  CAS  Google Scholar 

  • Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337: 331–37.

    Article  PubMed  CAS  Google Scholar 

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA (1999) Creation of human tumour cells with defined genetic elements. Nature 400: 464–68.

    Article  PubMed  CAS  Google Scholar 

  • Hayat MJ, Howlader N, Reichman ME, Edwards BK (2007) Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12: 20–37.

    Article  PubMed  Google Scholar 

  • Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14: 501–13.

    Article  PubMed  CAS  Google Scholar 

  • Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW, Blasco MA (1999) Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J 18(11): 2950–60.

    Article  PubMed  CAS  Google Scholar 

  • Jiang WQ, Zhong ZH, Henson JD, Reddel RR (2007) Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference. Oncogene 26(32):4635–47.

    Article  PubMed  CAS  Google Scholar 

  • Johnson JE, Varkonyi RJ, Schwalm J, Cragle R, Klein-Szanto A, Patchefsky A, Cukierman E, von Mehren M, Broccoli D (2005) Multiple mechanisms of telomere maintenance exist in liposarcomas. Clin Cancer Res 11: 5347–55.

    Article  PubMed  CAS  Google Scholar 

  • Ju Z, Rudolph KL (2006) Telomeres and telomerase in cancer stem cells. Eur J Cancer 42(9): 1197–203.

    Article  PubMed  CAS  Google Scholar 

  • Ju Z, Jiang H, Jaworski M, Gompf A, Rathinam C, Klein C, Trumpp A, Rudolph KL (2007) Telomere dysfunction induces environmental defects limiting hematopoietic stem/progenitor cell function and engraftment. Nature Med 13(6):742–7.

    Article  PubMed  CAS  Google Scholar 

  • Lechel A, Satyanarayana A, Ju Z, Plentz RR, Schaetzlein S, Rudolph C, Wilkens L, Wiemann SU, Saretzki G, Malek NP, Manns MP, Buer J, Rudolph KL (2005) The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo. EMBO Rep 6: 275–81.

    Article  PubMed  CAS  Google Scholar 

  • Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, Kubicka S, Schirmacher P, Jonkers J, Rudolph KL (2007) Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology, 132(4):1465–75.

    Article  PubMed  CAS  Google Scholar 

  • Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276: 561–67.

    Article  PubMed  CAS  Google Scholar 

  • Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432: 307–15.

    Article  PubMed  CAS  Google Scholar 

  • McEachern MJ, Krauskopf A, Blackburn EH (2000) Telomeres and their control. Annu Rev Genet 34: 331–58.

    Article  PubMed  CAS  Google Scholar 

  • Meeker AK, Hicks JL, Iacobuzio-Donahue CA, Montgomery EA, Westra WH, Chan TY, Ronnett BM, De Marzo AM (2004) Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin Cancer Res 10: 3317–26.

    Article  PubMed  CAS  Google Scholar 

  • Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90: 785–95.

    Article  PubMed  CAS  Google Scholar 

  • Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA (2005) Can chromosomal instability initiate tumorigenesis? Semin Cancer Biol 15: 43–49.

    Article  PubMed  CAS  Google Scholar 

  • Muntoni A, Reddel RR (2005) The first molecular details of ALT in human tumor cells. Hum Mol Genet 14: R191–96.

    Article  PubMed  CAS  Google Scholar 

  • O’Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, DePinho RA (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2: 149–55.

    Article  PubMed  Google Scholar 

  • O’Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S, Emond MJ, Gollahon KA, Moskovitz AH, Crispin DA, Potter JD, Rabinovitch PS (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32: 280–84.

    Article  PubMed  CAS  Google Scholar 

  • Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in ageing and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118(Pt 3): 485–96.

    Article  PubMed  CAS  Google Scholar 

  • Parsch D, Fellenberg J, Brummendorf TH, Eschlbeck AM, Richter W (2004) Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes. J Mol Med 82: 49–55.

    Article  PubMed  CAS  Google Scholar 

  • Plentz RR, Schlegelberger B, Flemming P, Gebel M, Kreipe H, Manns MP, Rudolph KL, Wilkens L (2005) Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma. Hepatology 42(3): 522–26.

    Article  PubMed  CAS  Google Scholar 

  • Plentz RR, Park YN, Lechel A, Kim H, Nellessen F, Langkopf BH, Wilkens L, Destro A, Fiamengo B, Manns MP, Roncalli M, Rudolph KL (2007) Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology 45: 968–76.

    Article  PubMed  CAS  Google Scholar 

  • Prowse KR, Greider CW (1995) Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA 92: 4818–22.

    Article  PubMed  CAS  Google Scholar 

  • Rudolph KL, Millard M, Bosenberg MW, DePinho RA (2001) Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 28: 155–59.

    Article  PubMed  CAS  Google Scholar 

  • Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in ageing telomerase-deficient mice. Cell 96(5): 701–12.

    Article  PubMed  CAS  Google Scholar 

  • Satyanarayana A, Manns MP, Rudolph KL (2004) Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology 40: 276–83.

    Article  PubMed  CAS  Google Scholar 

  • Shay JW, Wright WE (2002) Telomerase: a target for cancer therapeutics. Cancer Cell 2(4): 257–65.

    Article  PubMed  CAS  Google Scholar 

  • Tahara H, Yasui W, Tahara E, Fujimoto J, Ito K, Tamai K, Nakayama J, Ishikawa F, Tahara E, Ide T (1999) Immuno-histochemical detection of human telomerase catalytic component, hTERT, in human colorectal tumor and non-tumor tissue sections. Oncogene 18: 1561–67.

    Article  PubMed  CAS  Google Scholar 

  • van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GJ, Hicks JL, Wilentz RE, Goggins MG, De Marzo AM, Hruban RH, Maitra A (2002) Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol 161: 1541–47.

    PubMed  Google Scholar 

  • Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 91: 9857–60.

    Article  PubMed  CAS  Google Scholar 

  • Verdun RE, Karlseder J (2006) The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127: 709–20.

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Xie LY, Allan S, Beach D, Hannon GJ (1998) Myc activates telomerase. Genes Dev 12: 1769–74.

    Article  PubMed  CAS  Google Scholar 

  • Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, Rudolph KL (2002) Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 16: 935–42.

    Article  PubMed  CAS  Google Scholar 

  • Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, Alt FW, DePinho RA (2003) Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643–48.

    Article  PubMed  CAS  Google Scholar 

  • Wright WE, Shay JW (1992) The two-stage mechanism controlling cellular senescence and immortalization. Exp Gerontol 27(4): 383–89.

    Article  PubMed  CAS  Google Scholar 

  • Yui J, Chiu CP, Lansdorp PM (1998) Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 91: 3255–62.

    PubMed  CAS  Google Scholar 

  • Zhu J, Wang H, Bishop JM, Blackburn EH (1999) Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening. Proc Natl Acad Sci USA 96: 3723–28.

    Article  PubMed  CAS  Google Scholar 

  • Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM (2003) Lack of telomerase activity in human mesenchymal stem cells. Leukemia 17: 1146–49.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular Medicine and Max-Planck-Research-Group on Stem Cell, University of Ulm, Albert-Einstein-Allee 11, 89091, Ulm, Germany

    Dr. K. Lenhard Rudolph

Authors
  1. Dr. K. Lenhard Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Ulm, Albert-Einstein-Allee 11, 89091, Ulm, Germany

    K. Lenhard Rudolph

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Rudolph, K.L. (2008). Telomere Shortening and Telomerase Activation during Cancer Formation. In: Rudolph, K.L. (eds) Telomeres and Telomerase in Ageing, Disease, and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73709-4_11

Download citation

Publish with us

Policies and ethics

Search

Navigation