Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Apr 12;91(8):2900–2904. doi: 10.1073/pnas.91.8.2900

Telomerase activity in human ovarian carcinoma.

C M Counter 1, H W Hirte 1, S Bacchetti 1, C B Harley 1
PMCID: PMC43481  PMID: 8159676

Abstract

Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.

Full text

PDF
2900

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson D. J., King D. J., Haites N. E. Significant telomere shortening in childhood leukemia. Cancer Genet Cytogenet. 1992 Jul 15;61(2):204–206. doi: 10.1016/0165-4608(92)90088-p. [DOI] [PubMed] [Google Scholar]
  2. Allen H. J., Porter C., Gamarra M., Piver M. S., Johnson E. A. Isolation and morphologic characterization of human ovarian carcinoma cell clusters present in effusions. Exp Cell Biol. 1987;55(4):194–208. doi: 10.1159/000163419. [DOI] [PubMed] [Google Scholar]
  3. Allshire R. C., Dempster M., Hastie N. D. Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucleic Acids Res. 1989 Jun 26;17(12):4611–4627. doi: 10.1093/nar/17.12.4611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Allsopp R. C., Vaziri H., Patterson C., Goldstein S., Younglai E. V., Futcher A. B., Greider C. W., Harley C. B. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10114–10118. doi: 10.1073/pnas.89.21.10114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blackburn E. H. Structure and function of telomeres. Nature. 1991 Apr 18;350(6319):569–573. doi: 10.1038/350569a0. [DOI] [PubMed] [Google Scholar]
  6. Blackburn E. H. The molecular structure of centromeres and telomeres. Annu Rev Biochem. 1984;53:163–194. doi: 10.1146/annurev.bi.53.070184.001115. [DOI] [PubMed] [Google Scholar]
  7. Counter C. M., Avilion A. A., LeFeuvre C. E., Stewart N. G., Greider C. W., Harley C. B., Bacchetti S. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 1992 May;11(5):1921–1929. doi: 10.1002/j.1460-2075.1992.tb05245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Crickard K., Marinello M. J., Crickard U., Satchidanand S. K., Yoonessi M., Caglar H. Borderline malignant serous tumors of the ovary maintained on extracellular matrix: evidence for clonal evolution and invasive potential. Cancer Genet Cytogenet. 1986 Oct;23(2):135–143. [PubMed] [Google Scholar]
  9. GIRARDI A. J., JENSEN F. C., KOPROWSKI H. SV40-INDUCED TRANFORMATION OF HUMAN DIPLOID CELLS: CRISIS AND RECOVERY. J Cell Physiol. 1965 Feb;65:69–83. doi: 10.1002/jcp.1030650110. [DOI] [PubMed] [Google Scholar]
  10. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  11. Greider C. W., Blackburn E. H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature. 1989 Jan 26;337(6205):331–337. doi: 10.1038/337331a0. [DOI] [PubMed] [Google Scholar]
  12. Greider C. W., Blackburn E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985 Dec;43(2 Pt 1):405–413. doi: 10.1016/0092-8674(85)90170-9. [DOI] [PubMed] [Google Scholar]
  13. Harley C. B., Futcher A. B., Greider C. W. Telomeres shorten during ageing of human fibroblasts. Nature. 1990 May 31;345(6274):458–460. doi: 10.1038/345458a0. [DOI] [PubMed] [Google Scholar]
  14. Harley C. B. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991 Mar-Nov;256(2-6):271–282. doi: 10.1016/0921-8734(91)90018-7. [DOI] [PubMed] [Google Scholar]
  15. Hastie N. D., Dempster M., Dunlop M. G., Thompson A. M., Green D. K., Allshire R. C. Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990 Aug 30;346(6287):866–868. doi: 10.1038/346866a0. [DOI] [PubMed] [Google Scholar]
  16. Hirte H. W., Clark D. A., Mazurka J., O'Connell G., Rusthoven J. A rapid and simple method for the purification of tumor cells from ascitic fluid of ovarian carcinoma. Gynecol Oncol. 1992 Mar;44(3):223–226. doi: 10.1016/0090-8258(92)90046-l. [DOI] [PubMed] [Google Scholar]
  17. Hiyama E., Hiyama K., Yokoyama T., Ichikawa T., Matsuura Y. Length of telomeric repeats in neuroblastoma: correlation with prognosis and other biological characteristics. Jpn J Cancer Res. 1992 Feb;83(2):159–164. doi: 10.1111/j.1349-7006.1992.tb00081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Holzmann K., Blin N., Welter C., Zang K. D., Seitz G., Henn W. Telomeric associations and loss of telomeric DNA repeats in renal tumors. Genes Chromosomes Cancer. 1993 Mar;6(3):178–181. doi: 10.1002/gcc.2870060308. [DOI] [PubMed] [Google Scholar]
  19. Huschtscha L. I., Holliday R. Limited and unlimited growth of SV40-transformed cells from human diploid MRC-5 fibroblasts. J Cell Sci. 1983 Sep;63:77–99. doi: 10.1242/jcs.63.1.77. [DOI] [PubMed] [Google Scholar]
  20. Klingelhutz A. J., Barber S. A., Smith P. P., Dyer K., McDougall J. K. Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells. Mol Cell Biol. 1994 Feb;14(2):961–969. doi: 10.1128/mcb.14.2.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kruk P. A., Maines-Bandiera S. L., Auersperg N. A simplified method to culture human ovarian surface epithelium. Lab Invest. 1990 Jul;63(1):132–136. [PubMed] [Google Scholar]
  22. Lindsey J., McGill N. I., Lindsey L. A., Green D. K., Cooke H. J. In vivo loss of telomeric repeats with age in humans. Mutat Res. 1991 Jan;256(1):45–48. doi: 10.1016/0921-8734(91)90032-7. [DOI] [PubMed] [Google Scholar]
  23. Lundblad V., Szostak J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989 May 19;57(4):633–643. doi: 10.1016/0092-8674(89)90132-3. [DOI] [PubMed] [Google Scholar]
  24. Mehle C., Ljungberg B., Roos G. Telomere shortening in renal cell carcinoma. Cancer Res. 1994 Jan 1;54(1):236–241. [PubMed] [Google Scholar]
  25. Morin G. B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989 Nov 3;59(3):521–529. doi: 10.1016/0092-8674(89)90035-4. [DOI] [PubMed] [Google Scholar]
  26. Nürnberg P., Thiel G., Weber F., Epplen J. T. Changes of telomere lengths in human intracranial tumours. Hum Genet. 1993 Mar;91(2):190–192. doi: 10.1007/BF00222724. [DOI] [PubMed] [Google Scholar]
  27. Sack G. H., Jr Human cell transformation by simian virus 40--a review. In Vitro. 1981 Jan;17(1):1–19. doi: 10.1007/BF02618025. [DOI] [PubMed] [Google Scholar]
  28. Shay J. W., Wright W. E., Brasiskyte D., Van der Haegen B. A. E6 of human papillomavirus type 16 can overcome the M1 stage of immortalization in human mammary epithelial cells but not in human fibroblasts. Oncogene. 1993 Jun;8(6):1407–1413. [PubMed] [Google Scholar]
  29. Shay J. W., Wright W. E., Werbin H. Defining the molecular mechanisms of human cell immortalization. Biochim Biophys Acta. 1991 Apr 16;1072(1):1–7. doi: 10.1016/0304-419x(91)90003-4. [DOI] [PubMed] [Google Scholar]
  30. Smith J. K., Yeh G. Telomere reduction in endometrial adenocarcinoma. Am J Obstet Gynecol. 1992 Dec;167(6):1883–1887. doi: 10.1016/0002-9378(92)91791-8. [DOI] [PubMed] [Google Scholar]
  31. Vaziri H., Schächter F., Uchida I., Wei L., Zhu X., Effros R., Cohen D., Harley C. B. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993 Apr;52(4):661–667. [PMC free article] [PubMed] [Google Scholar]
  32. Yu G. L., Bradley J. D., Attardi L. D., Blackburn E. H. In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature. 1990 Mar 8;344(6262):126–132. doi: 10.1038/344126a0. [DOI] [PubMed] [Google Scholar]
  33. Zakian V. A. Structure and function of telomeres. Annu Rev Genet. 1989;23:579–604. doi: 10.1146/annurev.ge.23.120189.003051. [DOI] [PubMed] [Google Scholar]
  34. de Lange T., Shiue L., Myers R. M., Cox D. R., Naylor S. L., Killery A. M., Varmus H. E. Structure and variability of human chromosome ends. Mol Cell Biol. 1990 Feb;10(2):518–527. doi: 10.1128/mcb.10.2.518. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES