Abstract
Tumor cells with metastatie potential may have a high telomerase activity that augments telomeric DNA repeats, allowing the cells to escape from the inhibition of cell proliferation due to shortened telomeres. We examined the expression level of telomerase activity using the telomeric repeat amplification protocol among a series of cell lines obtained by repeated transplantation of a mouse fibrosarcoma. The lines could be grouped into three; one has no metastatic potential, and the other two show metastatic abilities after intravenous or subcutaneous injection. Comparison of their telomerase activity indicated that more malignant lines had higher activity. A similar relation was seen in metastatic nodules formed through clonal expansion from the heterogeneous population of inoculated cells; clonality was monitored in terms of variable patterns of subtelomeric repeats. The results suggest that a high level of telomerase activity may not be requisite for metastasis, but may confer a propensity to dominate in a tumor tissue.
Keywords: Telomere, Telomerase activity, Metastasis
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REFERENCES
- 1. ) Moyzis , R. K. , Buckingham , J. M. , Cram , S. , Dani , M. , Deaven , L. L. , James , M. D. , Meyne , J. , Ratliff , R. L. and Wu , J. R.A highly conserved repetitive DNA sequence, (TTAGGQ)n, present at the telomere of human chromosomes . Proc. Natl Acad, Sci. USA , 85 , 6622 – 6626 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. ) Blackburn , E. H.Structure and function of telomeres . Nature , 350 , 569 – 573 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Zakian , V. A.Structure and function of telomeres , Annu. Rev. Genet. , 23 , 579 – 604 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Rhyu , M. S.Telomeres, telomerase, and immortality . J. Natl. Cancer Inst. , 87 , 884 – 895 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Harley , C. B. , Futcher , A. B. and Greider , C. W.Telomeres shorten during aging of human fibroblasts . Nature , 345 , 458 – 460 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Hastie , N. D. , Dempster , M. , Dunlop , M. G. , Thompson , A. M. , Green , D. K. and Allshire , R. C.Telomere reduction in human colorectal carcinoma and with aging , Nature , 346 , 866 – 868 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Lundbald , V. and Szostak , J. W.A mutant with a defect in telomere elongation leads to senescence in yeast . Cell , 57 , 633 – 643 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Greider , C. W. and Blackburn , E. H.The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity . Cell , 51 , 887 – 898 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Morin , G. B.The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats . Cell , 59 , 521 – 529 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Kim , N. W. , Piatyszek , M. A. , Prowse , K. R. , Harley , C. B. , West , M. D. , Ho , P. L. C. , Coviello , G. M. , Wright , W. E. , Weinrich , S. L. and Shay , J. W.Specific association of human telomerase activity with immortal cells and cancer . Science , 266 , 2011 – 2015 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Counter , C. M. , Hirte , H. W. , Bacchetti , S. and Halrey , C.Telomerase activity in human ovarian carcinoma . Proc. Natl. Acad. Sci. USA , 91 , 2900 – 2904 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. ) Hiyama , K. , Hiyama , E. , Ishioka , S. , Yamada , M. , Inai , K. , Gazdar , A. F. , Piatyszek , M. A. and Shay , J. W.Telomerase activity in small‐cell and non‐small‐cell lung cancers . J Natl. Cancer Inst. , 87 , 895 – 902 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Chadeneau , C. , Hay , K. , Hirte , H. W. , Steven , G. and Silvia , B.Telomerase activity associated with acquisition of malignancy in human colorectal cancer . Cancer Res. , 55 , 2533 – 2536 ( 1995. ). [PubMed] [Google Scholar]
- 14. ) Tahara , H. , Nakanishi , T. , Kitamoto , M. , Nakashio , R. , Shay , J. W. , Tahara , E. , Kajiyama , G. and Ide , T.Telomerase activity in human liver tissues: comparison between chronic liver disease and hepatocellular carcinomas . Cancer Res. , 55 , 2734 – 2736 ( 1995. ). [PubMed] [Google Scholar]
- 15. ) Hiyama , E. , Yokoyama , T. , Tatsumoto , N. , Hiyama , K. , Imamura , Y. , Murakami , Y. , Kodama , T. , Piatyszek , M. A. , Shay , J. W. and Matsuura , Y.Telomerase activity in gastric cancer . Cancer Res. , 55 , 3258 – 3262 ( 1995. ). [PubMed] [Google Scholar]
- 16. ) Hiyama , E. , Gollahon , L. , Takaoka , T. and Shay , J.Telomerase activity in human breast tumors . J. Natl. Cancer Inst. , 88 , 116 – 122 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Hiyama , K. , Hirai , Y. , Kyoizumi , S. , Akiyama , M. , Hiyama , E. , Piatyszek , M. A. , Shay , J. W. , Ishikawa , S. and Yamada , M.Activation of telomerase in human lymphocytes and hematopoietic progenitor . J. Immunol. , 155 , 3711 – 3715 ( 1995. ). [PubMed] [Google Scholar]
- 18. ) Broccoli , D. , Youneg , J. W. and de Lange , T.Telomerase activity in normal and malignant hematopoietic cells . Proc. Natl. Acad. Sci. USA , 92 , 9082 – 9086 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. ) Hiyama , E. , Hiyama , K. , Yokoyama , T. , Yokoyama , T. , Matsuura , Y. , Piatyszek , M. A. and Shay , J. W.Correlating telomerase activity levels with human neuroblastoma outcomes . Nat. Med. , 1 , 249 – 255 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Chadeneau , C. , Siegel , P. , Harley , C. B. , Muller , W. J. and Bacchetti , S.Telomerase activity in normal and malignant murine tissues . Oncogene , 11 , 893 – 898 ( 1995. ). [PubMed] [Google Scholar]
- 21. ) Broccoli , D. , Godley , L. A. , Donehower , L. A. , Varmus , H. E. and de Lange , T.Telomerase activation in mouse mammary tumors: lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation . Mol. Cell. Biol. , 16 , 3765 – 3772 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. ) Blasco , M. , Rizen , M. , Greider , C. W. and Hanahan , D.Differential regulation of telomerase activity and telomerase RNA during multi‐stage tumorigenesis . Nat. Genet. , 12 , 200 – 204 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Ogoshi , M. , Takashima , A. and Taylor , R. S.Mechanisms regulating telomere activity in murine T cells . J. Immunol. , 158 , 622 – 628 ( 1997. ). [PubMed] [Google Scholar]
- 24. ) Ohtsuka , H. , Mafune , Y. , Tsunashima , K. , Takahashi , H. and Kominami , R.Difference in allelic expression of genes probably associated with tumor progression in murine fibrosarcomas and cell lines . Jpn. J. Cancer Res. , 85 , 1015 – 1022 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. ) Ohyashiki , J. H. , Ohyashiki , K. , Sano , T. and Toyama , K.Non‐radioisotopic and semi‐quantitative procedure for terminal repeat amplification protocol . Jpn. J. Cancer Res. , 87 , 329 – 331 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. ) Hayashi , T. , Mafune , Y. , Takada , T. , Hatakeyama , K. , Takagi , N. and Kominami , R.Telomere change and loss of heterozygosity of mouse primary tumors and cell lines . Jpn. J. Cancer Res. , 84 , 1292 – 1299 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. ) Hayashi , T. , Ohtsuka , H. , Kuwabara , K , Mafune , Y , Miyashita , N. , Moriwaki , K. , Takahashi , Y. and Kominami , R.A variant family of mouse minor satellite located on the centromeric region of chromosome 2 . Genomics , 17 , 490 – 492 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 28. ) Mitani , K. , Takahashi , Y. and Kominami , R.A GGCAGG motif in minisatellites affecting their germline instability . J. Biol. Chem. , 265 , 15203 – 15210 ( 1990. ). [PubMed] [Google Scholar]
- 29. ) Kipling , D. and Cooke , H. J.Hypervariable ultra‐long telomeres in mice . Nature , 347 , 400 – 402 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 30. ) Starling , J. A. , Maule , J. , Hastie , N. D. and Allshire , R. C.Extensive telomere repeat arrays in mouse are hypervariable . Nucleic Acids Res. , 18 , 6881 – 6888 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. ) Kipling , D. , Ackford , H. E. , Taylor , B. A. and Cooke , H. J.Mouse minor satellite DNA genetically maps to the centromere and is physically linked to the proximal telomere . Genomics , 11 , 235 – 241 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 32. ) Nowell , P.Mechanisms of tumor progression . Cancer Res. , 46 , 2203 – 2207 ( 1986. ). [PubMed] [Google Scholar]
- 33. ) Wainscoat , J. S. and Fey , M. F.An assessment of clonality in human tumors: a review . Cancer Res. , 50 , 1355 – 1360 ( 1990. ). [PubMed] [Google Scholar]
- 34. ) Mafune , Y. , Asakura , H. and Kominami , R.Allelic losses and metastatic ability of mouse tumor cell clones derived from a heterozygous mouse . Oncogene , 9 , 2191 – 2196 ( 1994. ). [PubMed] [Google Scholar]
- 35. ) Holt , S. H. , Wright , W. and Shay , J. W.Regulation of telomerase activity in immortal cell lines . Mol. Cell. Biol , 16 , 2932 – 2939 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. ) Chadeneau , C. , Siegel , P. , Harley , C. B. , Müller , J. W. and Bacchetti , S.Telomerase activity in normal and malignant murine tissues . Oncogene , 11 , 893 – 898 ( 1995. ). [PubMed] [Google Scholar]
- 37. ) Burger , A. M. , Bibby , M. C. and Double , J. A.Telomerase activity in normal and malignant mammalian tissues: feasibility of telomerase as a target for cancer chemotherapy . Br. J. Cancer , 75 , 516 – 522 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. ) Zakian , V. A.Saccharomyces telomeres: function, structure and replication . In “ Telomeres ,” ed. Blackburn E. H. and Greider C. W. , pp. 107 – 138 ( 1995. ). Cold Spring Harbor Laboratory Press; , Cold Spring Harbor , N.Y . [Google Scholar]
- 39. ) Conrad , M. N. , Wright , J. H. , Wolf , A. J. and Zakian , A.RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability . Cell , 63 , 739 – 750 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 40. ) Sandell , L. L. and Zakian , V. A.Loss of yeast telomere: arrest, recovery, and chromosome loss . Cell , 75 , 729 – 739 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 41. ) de Lange , T.Activation of telomerase in a human tumor . Proc. Natl Acad. Sci. USA , 91 , 2882 – 2885 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. ) van Steensel , B. and de Lange , T.Control of telomere length by the human telomere binding protein TRF1 . Nature , 385 , 740 – 743 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 43. ) Kyrion , G. , Boakye , K. A. and Lustig , A. J.C‐Terminal truncation of RAP1 results in the deregulatation of telomere size, stability, and function in Saccharomyces cerevisiae. Mol. Cell. Biol , 12 , 5159 – 5173 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. ) Greenwell , P. W. , Kronmal , S. L. , Porter , S. E. , Gassenhuber , J. , Obermaier , B. and Peters , T. D.TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene . Cell , 82 , 823 – 829 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 45. ) Cooper , J. P. , Nimmo , E. R. , Allshire , R. C. and Cech , T. R.Regulation of telomere length and function by a Myb‐domain protein in fission yeast . Nature , 385 , 744 – 747 ( 1997. ). [DOI] [PubMed] [Google Scholar]