تلومراز و درمان تومورهای مغزی

نوع مقاله : Review Article

نویسندگان

1 استادیار، مرکز تحقیقات بیماری‌های ارثی کودکان و گروه ژنتیک و بیولوژی مولکولی، دانشکده‌ی پزشکی، دانشگاه علوم پزشکی اصفهان، اصفهان، ایران

2 دانشجوی کارشناسی ارشد، گروه ژنتیک و بیولوژی مولکولی، دانشکده‌ی پزشکی و کمیته‌ی تحقیقات دانشجویی، دانشگاه علوم پزشکی اصفهان، اصفهان، ایران

چکیده

تلومر یک ساختمان ویژه می‌باشد که سبب محافظت انتهای کروموزوم از تحلیل رفتن می‌شود. تلومر در هر بار تقسیم سلولی کوتاه‌تر می‌شود. با این حال، تلومراز آنزیمی است که در سلول‌های سرطانی و رده‌ی زاینده فعال است که تلومر را بازسازی می‌کند. اما در ظاهر ارتباطی بین طول تلومر و فعالیت تلومراز وجود ندارد. فعالیت آنزیم تلومراز با بدخیمی تومور در ارتباط است. به طور کلی، فعالیت تلومراز و درجه‌ی هیستولوژیکی ارتباط نزدیکی با هم دارند و نتیجه‌ی مطالعات مشخص نموده است که فعالیت تلومراز، یک نشانگر مهم بدخیمی در تومورهای مغزی است. به عنوان نتیجه‌گیری نهایی، می‌توان گفت احتمال می‌رود که فعالیت تلومراز می‌تواند به عنوان نشانگر بیولوژیکی در پاسخ به درمان در نظر گرفته شود.

کلیدواژه‌ها

عنوان مقاله [English]

Telomerase and Therapy of Brain Tumors

نویسندگان [English]

  • Majid Kheirollahi 1
  • Roya Khajeh-Goodari 2
  • Reza Ghavimi 2
1 Assistant Professor, Pediatrics Inherited Diseases Research Center AND Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 MSc Student, Department of Genetics and Molecular Biology, School of Medicine AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
چکیده [English]

Telomere is a special structure protects the ends of human chromosomes to degrade. Telomere becomes shorter after each cycle of cell division. However, telomerase is an enzyme activated in cancer cells and germ lines rebuild telomere. However, apparently there is no correlation between telomere length and telomerase activity. The enzymatic activity of telomerase correlates with tumor malignancy. In general, telomerase activity and histological grade are too closely correlated and the results of studies indicate that telomerase activity may be an important malignancy marker in brain tumors. As a conclusion, we can say that activity of telomerase should be considered as a prognostic biological marker of response to treatment.

کلیدواژه‌ها [English]

  • Telomerase
  • Therapy
  • Brain tumors

مراجع

  1. Allshire RC, Dempster M, Hastie ND. Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucleic Acids Res 1989; 17(12): 4611-27.
  2. Buchkovich KJ, Greider CW. Telomerase regulation during entry into the cell cycle in normal human T cells. Mol Biol Cell 1996; 7(9): 1443-54.
  3. Wang JC, Warner JK, Erdmann N, Lansdorp PM, Harrington L, Dick JE. Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc Natl Acad Sci U S A 2005; 102(40): 14398-403.
  4. Hahn WC. Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol 2003; 21(10): 2034-43.
  5. Sedivy JM. Can ends justify the means?: telomeres and the mechanisms of replicative senescence and immortalization in mammalian cells. Proc Natl Acad Sci U S A 1998; 95(16): 9078-81.
  6. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006; 127(4): 679-95.
  7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646-74.
  8. Hsu CP, Ko JL, Shai SE, Lee LW. Modulation of telomere shelterin by TRF1 [corrected] and TRF2 interacts with telomerase to maintain the telomere length in non-small cell lung cancer. Lung Cancer 2007; 58(3): 310-6.
  9. van SB, de LT. Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385(6618): 740-3.
  10. Kheirollahi M. Telomere, regulation and tumorigenesis. In: Mehdipour P. Telomere terittory and cancer. New Yok, NY: Springer; 2013. p. 55-99.
  11. van SB, Smogorzewska A, de LT. TRF2 protects human telomeres from end-to-end fusions. Cell 1998; 92(3): 401-13.
  12. Ancelin K, Brunori M, Bauwens S, Koering CE, Brun C, Ricoul M, et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol Cell Biol 2002; 22(10): 3474-87.
  13. La TD, de DO, Conti A, Angileri FF, Cardali S, Aguennouz M, et al. Expression of telomeric repeat binding factor-1 in astroglial brain tumors. Neurosurgery 2005; 56(4): 802-10.
  14. Alonso MM, Fueyo J, Shay JW, Aldape KD, Jiang H, Lee OH, et al. Expression of transcription factor E2F1 and telomerase in glioblastomas: mechanistic linkage and prognostic significance. J Natl Cancer Inst 2005; 97(21): 1589-600.
  15. Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002; 2(12): 910-7.
  16. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, Russell JL, Conti CJ, Johnson DG. E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model. Mol Cell Biol 1999; 19(9): 6408-14.
  17. DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A 1997; 94(14): 7245-50.
  18. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, et al. Telomerase maintains telomere structure in normal human cells. Cell 2003; 114(2): 241-53.
  19. Won J, Chang S, Oh S, Kim TK. Small-molecule-based identification of dynamic assembly of E2F-pocket protein-histone deacetylase complex for telomerase regulation in human cells. Proc Natl Acad Sci U S A 2004; 101(31): 11328-33.
  20. Xiang H, Wang J, Mao Y, Liu M, Reddy VN, Li DW. Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway. Oncogene 2002; 21(23): 3784-91.
  21. Zhao J, Bilsland A, Hoare SF, Keith WN. Involvement of NF-Y and Sp1 binding sequences in basal transcription of the human telomerase RNA gene. FEBS Lett 2003; 536(1-3): 111-9.
  22. Langford LA, Piatyszek MA, Xu R, Schold SC, Jr., Shay JW. Telomerase activity in human brain tumours. Lancet 1995; 346(8985): 1267-8.
  23. Hakin-Smith V, Jellinek DA, Levy D, Carroll T, Teo M, Timperley WR, et al. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 2003; 361(9360): 836-8.
  24. Philippi C, Loretz B, Schaefer UF, Lehr CM. Telomerase as an emerging target to fight cancer--opportunities and challenges for nanomedicine. J Control Release 2010; 146(2): 228-40.
  25. Shay JW, Wright WE. Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov 2006; 5(7): 577-84.
  26. Hiyama E, Hiyama K. Telomerase as tumor marker. Cancer Lett 2003; 194(2): 221-33.
  27. Dasi F, Lledo S, Garcia-Granero E, Ripoll R, Marugan M, Tormo M, et al. Real-time quantification in plasma of human telomerase reverse transcriptase (hTERT) mRNA: a simple blood test to monitor disease in cancer patients. Lab Invest 2001; 81(5): 767-9.
  28. Kanyama Y, Hibi K, Nakayama H, Kodera Y, Ito K, Akiyama S, et al. Detection of p16 promoter hypermethylation in serum of gastric cancer patients. Cancer Sci 2003; 94(5): 418-20.
  29. Hiyama K, Ishioka S, Shay JW, Taooka Y, Maeda A, Isobe T, et al. Telomerase activity as a novel marker of lung cancer and immune-associated lung diseases. Int J Mol Med 1998; 1(3): 545-9.
  30. Yi X, White DM, Aisner DL, Baur JA, Wright WE, Shay JW. An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Neoplasia 2000; 2(5): 433-40.
  31. Bieche I, Nogues C, Paradis V, Olivi M, Bedossa P, Lidereau R, et al. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 2000; 6(2): 452-9.
  32. Lord RV, Salonga D, Danenberg KD, Peters JH, DeMeester TR, Park JM, et al. Telomerase reverse transcriptase expression is increased early in the Barrett's metaplasia, dysplasia, adenocarcinoma sequence. J Gastrointest Surg 2000; 4(2): 135-42.
  33. Kotoula V, Hytiroglou P, Pyrpasopoulou A, Saxena R, Thung SN, Papadimitriou CS. Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers. Liver 2002; 22(1): 57-69.
  34. Greenberg RA, O'Hagan RC, Deng H, Xiao Q, Hann SR, Adams RR, et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 1999; 18(5): 1219-26.
  35. Yi X, Shay JW, Wright WE. Quantitation of telomerase components and hTERT mRNA splicing patterns in immortal human cells. Nucleic Acids Res 2001; 29(23): 4818-25.
  36. Harada K, Kurisu K, Tahara H, Tahara E, Ide T, Tahara E. Telomerase activity in primary and secondary glioblastomas multiforme as a novel molecular tumor marker. J Neurosurg 2000; 93(4): 618-25.
  37. Kleinschmidt-Demasters BK, Evans LC, Bobak JB, Lopez-Uribe D, Hopper D, Shroyer AL, et al. Quantitative telomerase expression in glioblastomas shows regional variation and down-regulation with therapy but no correlation with patient outcome. Hum Pathol 2000; 31(8): 905-13.
  38. Sugita Y, Nakashima A, Kato S, Sakata K, Morimatsu M, Shigemori M. Telomerase activity in gliomas with the use of non-radioisotopic and semi-quantitative procedure for terminal repeat amplification protocol. Oncol Rep 2000; 7(5): 1087-92.
  39. Krams M, Hero B, Berthold F, Parwaresch R, Harms D, Rudolph P. Full-length telomerase reverse transcriptase messenger RNA is an independent prognostic factor in neuroblastoma. Am J Pathol 2003; 162(3): 1019-26.
  40. Shay JW, Keith WN. Targeting telomerase for cancer therapeutics. Br J Cancer 2008; 98(4): 677-83.
  41. Shervington A, Pawar V, Menon S, Thakkar D, Patel R. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Mol Biol Rep 2009; 36(5): 1181-6.
  42. Ito H, Aoki H, Kuhnel F, Kondo Y, Kubicka S, Wirth T, et al. Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus. J Natl Cancer Inst 2006; 98(9): 625-36.
  43. Patel R, Shervington L, Lea R, Shervington A. Epigenetic silencing of telomerase and a non-alkylating agent as a novel therapeutic approach for glioma. Brain Res 2008; 1188: 173-81.
  44. Shervington A, Patel R. Silencing DNA methyltransferase (DNMT) enhances glioma chemosensitivity. Oligonucleotides 2008; 18(4): 365-74.
  45. Tabori U, Wong V, Ma J, Shago M, Alon N, Rutka J, et al. Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma. Br J Cancer 2008; 99(7): 1129-35.
  46. Zhang Z, Yang X, Zhang Y, Zeng B, Wang S, Zhu T, et al. Delivery of telomerase reverse transcriptase small interfering RNA in complex with positively charged single-walled carbon nanotubes suppresses tumor growth. Clin Cancer Res 2006; 12(16): 4933-9.
  47. Xia Y, Lin RX, Zheng SJ, Yang Y, Bo XC, Zhu DY, et al. Effective siRNA targets screening for human telomerase reverse transcriptase. World J Gastroenterol 2005; 11(16): 2497-501.
  48. Ludwig A, Saretzki G, Holm PS, Tiemann F, Lorenz M, Emrich T, et al. Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res 2001; 61(7): 3053-61.
  49. Yokoyama Y, Takahashi Y, Shinohara A, Wan X, Takahashi S, Niwa K, et al. The 5'-end of hTERT mRNA is a good target for hammerhead ribozyme to suppress telomerase activity. Biochem Biophys Res Commun 2000; 273(1): 316-21.
  50. Kyo S, Inoue M. Complex regulatory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene 2002; 21(4): 688-97.
  51. De CA, Cristofari G, Reichenbach P, De LE, Monchaud D, Teulade-Fichou MP, et al. Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action. Proc Natl Acad Sci U S A 2007; 104(44): 17347-52.
  52. Tan JH, Gu LQ, Wu JY. Design of selective G-quadruplex ligands as potential anticancer agents. Mini Rev Med Chem 2008; 8(11): 1163-78.
  53. Burger AM, Dai F, Schultes CM, Reszka AP, Moore MJ, Double JA, et al. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res 2005; 65(4): 1489-96.
  54. Tan JH, Ou TM, Hou JQ, Lu YJ, Huang SL, Luo HB, et al. Isaindigotone derivatives: a new class of highly selective ligands for telomeric G-quadruplex DNA. J Med Chem 2009; 52(9): 2825-35.
  55. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, et al. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 1999; 5(10): 1164-70.
  56. Fletcher TM, Cathers BE, Ravikumar KS, Mamiya BM, Kerwin SM. Inhibition of human telomerase by 7-deaza-2'-deoxyguanosine nucleoside triphosphate analogs: potent inhibition by 6-thio-7-deaza-2'-deoxyguanosine 5'-triphosphate. Bioorg Chem 2001; 29(1): 36-55.
  57. Rosenberg SA. Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol Today 1997; 18(4): 175-82.
  58. Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183(3): 725-9.
  59. Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001; 411(6835): 380-4.
  60. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM. The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity 1999; 10(6): 673-9.
  61. Schmidt J, Ryschich E, Sievers E, Schmidt-Wolf IG, Buchler MW, Marten A. Telomerase-specific T-cells kill pancreatic tumor cells in vitro and in vivo. Cancer 2006; 106(4): 759-64.
  62. Jiang F, Bao J, Li P, Nicosia SV, Bai W. Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase. J Biol Chem 2004; 279(51): 53213-21.
  63. Zaffaroni N, Lualdi S, Villa R, Bellarosa D, Cermele C, Felicetti P, et al. Inhibition of telomerase activity by a distamycin derivative: effects on cell proliferation and induction of apoptosis in human cancer cells. Eur J Cancer 2002; 38(13): 1792-801.
  64. Moriscot C, de FF, Richard MJ, Marchand M, Savatier P, Bosco D, et al. Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 2005; 23(4): 594-603.
  65. Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 1996; 5(3): 207-16.
  66. Ohyashiki JH, Sashida G, Tauchi T, Ohyashiki K. Telomeres and telomerase in hematologic neoplasia. Oncogene 2002; 21(4): 680-7.
  67. Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, et al. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 2002; 20(6): 592-6.
  68. Sugihara M, Ohshima K, Nakamura H, Suzumiya J, Nakayama Y, Kanda M, et al. Decreased expression of telomerase-associated RNAs in the proliferation of stem cells in comparison with continuous expression in malignant tumors. Int J Oncol 1999; 15(6): 1075-80.
  69. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413(6854): 432-5.
  70. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367(6464): 645-8.
  71. Liu L, DiGirolamo CM, Navarro PA, Blasco MA, Keefe DL. Telomerase deficiency impairs differentiation of mesenchymal stem cells. Exp Cell Res 2004; 294(1): 1-8.
  72. Meerdo LN, Reed WA, White KL. Telomere-to-centromere ratio of bovine clones, embryos, gametes, fetal cells, and adult cells. Cloning Stem Cells 2005; 7(1): 62-73.
  73. Meirelles LS, Nardi NB. Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Br J Haematol 2003; 123(4): 702-11.
  74. Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 2005; 436(7053): 1048-52.
  75. Wright LS, Prowse KR, Wallace K, Linskens MH, Svendsen CN. Human progenitor cells isolated from the developing cortex undergo decreased neurogenesis and eventual senescence following expansion in vitro. Exp Cell Res 2006; 312(11): 2107-20.
  76. Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 1993; 52(4): 661-7.
  77. Wynn RF, Cross MA, Hatton C, Will AM, Lashford LS, Dexter TM, et al. Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants. Lancet 1998; 351(9097): 178-81.
  78. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 2005; 123(6): 1121-31.
  79. Shervington A, Patel R. Differential hTERT mRNA processing between young and older glioma patients. FEBS Lett 2008; 582(12): 1707-10.
  80. Poremba C, Heine B, Diallo R, Heinecke A, Wai D, Schaefer KL, et al. Telomerase as a prognostic marker in breast cancer: high-throughput tissue microarray analysis of hTERT and hTR. J Pathol 2002; 198(2): 181-9.
  81. La TD, Conti A, Aguennouz MH, De Pasquale MG, Romeo S, Angileri FF, et al. Telomere length modulation in human astroglial brain tumors. PLoS One 2013; 8(5): e64296.
  82. Kheirollahi M, Mehrazin M, Kamalian N, Mohammadi-asl J, Mehdipour P. Telomerase activity in human brain tumors: astrocytoma and meningioma. Cell Mol Neurobiol 2013; 33(4): 569-74.
  83. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990; 346(6287): 866-8.
  84. Kheirollahi M, Mehrazin M, Kamalian N, Mehdipour P. Alterations of telomere length in human brain tumors. Med Oncol 2011; 28(3): 864-70.
  85. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361(9355): 393-5.
  86. Londono-Vallejo JA, Der-Sarkissian H, Cazes L, Bacchetti S, Reddel RR. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res 2004; 64(7): 2324-7.
  87. Chen HJ, Cho CL, Liang CL, Chen L, Chang HW, Lu K, et al. Differential telomerase expression and telomere length in primary intracranial tumors. Chang Gung Med J 2001; 24(6): 352-60.
  88. Chen HJ, Cho CL, Liang CL, Lu K, Lin JW. Implication of telomere length as a proliferation-associated marker in schwannomas. J Surg Oncol 2002; 81(2): 93-100.
مجله دانشکده پزشکی اصفهان
دوره 31، شماره 267 - شماره پیاپی 267
بهمن و اسفند 1392
صفحه 2193-2208

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  • تاریخ دریافت: 29 آذر 1392
  • تاریخ بازنگری: 06 اردیبهشت 1403
  • تاریخ پذیرش: 17 فروردین 1401

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