Abstract
Telomere maintenance is regarded as a key mechanism in overcoming cellular senescence in tumor cells and in most cases is achieved by the activation of telomerase. However there is at least one alternative mechanism of telomere lengthening (ALT) which is characterized by heterogeneous and elongated telomeres in the absence of telomerase activity (TA). We evaluated the prevalence of TA, gene expression of telomerase subunits and ALT in relation to telomere morphology and function in matrix producing bone tumors and in osteosarcoma cell lines and present evidence of a direct association of ALT with telomere dysfunction and chromosomal instability. Telomere fluorescence in situ hybridization (T-FISH) in ALT cells revealed elongated and shortened telomeres, partly in unusual configurations and loci, dicentric marker chromosomes and signal-free chromosome ends. Free ends give rise to end-to-end associations and may induce breakage-fusion-bridge cycles resulting in an increased number of complex chromosomal rearrangements, as detected by multiplex-FISH (M-FISH). We propose that ALT cannot be seen as an equivalent to telomerase activity in telomere maintenance. Its association with telomere dysfunction and chromosomal instability may have major implications for tumor progression.
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References
Aue G, Muralidhar B, Schwartz HS, Butler MG . 1998 Ann. Surg. Oncol. 5: 627–634
Autexier C, Greider CW . 1996 Trends Biochem. Sci. 21: 387–391
Avilion AA, Piatyszek MA, Gupta J, Shay JW, Bacchetti S, Greider CW . 1996 Cancer Res. 56: 645–650
Biessmann H, Mason JM . 1997 Chromosoma 106: 63–69
Bouffler SD, Morgan WF, Pandita TK, Slijepcevic P . 1996 Mutat. Res. 366: 129–135
Brinkschmidt C, Poremba C, Christiansen H, Simon R, Schafer KL, Terpe HJ, Lampert F, Boecker W, Dockhorn-Dworniczak B . 1998 Br. J. Cancer 77: 2223–2229
Broccoli D, Young JW, de LT . 1995 Proc. Natl. Acad. Sci. USA 92: 9082–9086
Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR . 1997 Nat. Med. 3: 1271–1274
Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR . 1995 EMBO J. 14: 4240–4248
Bryce LA, Morrison N, Hoare SF, Muir S, Keith WN . 2000 Neoplasia 2: 197–201
Chen PL, Chen YM, Bookstein R, Lee WH . 1990 Science 250: 1576–1580
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S . 1992 EMBO J. 11: 1921–1929
Counter CM, Gupta J, Harley CB, Leber B, Bacchetti S . 1995 Blood 85: 2315–2320
Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM, Weinberg RA . 1998 Proc. Natl. Acad. Sci. USA 95: 14723–14728
Ducray C, Pommier JP, Martins L, Boussin FD, Sabatier L . 1999 Oncogene 18: 4211–4223
Eils R, Uhrig S, Saracoglu K, Satzler K, Bolzer A, Petersen I, Chassery J, Ganser M, Speicher MR . 1998 Cytogenet. Cell. Genet. 82: 160–171
Greider CW, Blackburn EH . 1987 Cell 51: 887–898
Harle BC, Boukamp P . 1996 Proc. Natl. Acad. Sci. USA 93: 6476–6481
Hiyama E, Hiyama K, Tatsumoto N, Kodama T, Shay JW, Yokoyama T . 1996 Int. J. Oncol. 9: 453–458
Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M . 1995 J. Immunol. 155: 3711–3715
Ito H, Kyo S, Kanaya T, Takakura M, Inoue M, Namiki M . 1998 Clin. Cancer Res. 4: 1603–1608
Kass-Eisler A, Greider CW . 2000 Trends Biochem. Sci. 25: 200–204
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW . 1994 Science 266: 2011–2015
Landers JE, Cassel SL, George DL . 1997 Cancer Res. 57: 3562–3568
Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, Dirks RW, Raap AK, Tanke HJ . 1996 Hum. Mol. Genet. 5: 685–691
McClintock B . 1941 Genetics 26: 234–282
Melek M, Shippen DE . 1996 Bioessays 18: 301–308
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 Cell 90: 785–795
Mitchell JR, Wood E, Collins K . 1999 Nature 402: 551–555
Olovnikov AM . 1971 Dokl Akad Nauk. 201: 1496–1499
Perrem K, Bryan TM, Englezou A, Hackl T, Moy EL, Reddel RR . 1999 Oncogene 18: 3383–3390
Poremba C, Bocker W, Willenbring H, Schafer KL, Otterbach F, Burger H, Diallo R, Dockhorn DB . 1998 Int. J. Oncol. 12: 641–648
Poremba C, Scheel C, Hero B, Christiansen H, Schaefer KL, Nakayama J, Berthold F, Juergens H, Boecker W, Dockhorn-Dworniczak B . 2000 J. Clin. Oncol. 18: 2582–2592
Poremba C, Shroyer KR, Frost M, Diallo R, Fogt F, Schäfer K, Bürger H, Shroyer AL, Dockhorn-Dworniczak B, Boecker W . 1999 J. Clin. Oncol. 17: 2020–2026
Radig K, Schneider-Stock R, Haeckel C, Neumann W, Roessner A . 1998 Hum. Pathol. 29: 1310–1316
Ramakrishnan S, Eppenberger U, Mueller H, Shinkai Y, Narayanan R . 1998 Cancer Res. 58: 622–625
Romano JW, Ehrhart JC, Duthu A, Kim CM, Appella E, May P . 1989 Oncogene 4: 1483–1488
Shay JW . 1999 J. Natl. Cancer Inst. 91: 4–6
Shay JW, Bacchetti S . 1997 Eur. J. Cancer 33: 787–791
Speicher MR, Gwyn BS, Ward DC . 1996 Nat. Genet. 12: 368–375
Sumida T, Hamakawa H, Sogawa K, Sugita A, Tanioka H, Ueda N . 1999 Int. J. Cancer 80: 1–4
Takakura M, Kyo S, Kanaya T, Tanaka M, Inoue M . 1998 Cancer Res. 58: 1558–1561
Takubo K, Nakamura K, Izumiyama N, Mafune K, Tanaka Y, Miyashita M, Sasajima K, Kato M, Oshimura M . 1997 J. Surg. Oncol. 66: 88–92
Tanaka H, Shimizu M, Horikawa I, Kugoh H, Yokota J, Barrett JC, Oshimura M . 1998 Genes Chromosomes Cancer 23: 123–133
Watson JD . 1972 Nat. New Biol. 239: 197–201
Wright WE, Brasiskyte D, Piatyszek MA, Shay JW . 1996 EMBO J. 15: 1734–1741
Wright WE, Pereira SO, Shay JW, et al. 1989 Mol. Cell. Biol. 9: 3088–3092
Wynford-Thomas D . 1999 J. Pathol. 187: 100–111
Zhu X, Kumar R, Mandal M, Sharma N, Sharma HW, Dhingra U, Sokoloski JA, Hsiao R, Narayanan R . 1996 Proc. Natl. Acad. Sci. USA 93: 6091–6095
Acknowledgements
We would like to thank Dagmar Haves, Frauke Schmidt, Petra Meier and Lydia Grote for excellent technical assistance. We would also like to thank Andreas Scheel for useful advice. Supported in part by the German Research Foundation “Deutsche Forschungsgemeinschaft DFG” (grant nos. Po. 529/4-1 and Po. 529/5-1) and the IZKF Muenster (grant nos. G2 and H2).
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Scheel, C., Schaefer, KL., Jauch, A. et al. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene 20, 3835–3844 (2001). https://doi.org/10.1038/sj.onc.1204493
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DOI: https://doi.org/10.1038/sj.onc.1204493
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