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DOI: 10.1055/s-2000-8252
Telomeraseaktivität beim Bronchialkarzinom[1] [2]
Der Nachweis des „Unsterblichkeitsenzyms” in Bürstenbiopsien erhöht die diagnostische Ausbeute bei Verdacht auf ein peripheres KarzinomPublication History
Publication Date:
31 December 2000 (online)
Zusammenfassung:
Die Replikationsfähigkeit normaler somatischer Zellen ist zeitlich begrenzt durch den zunehmenden Verlust ihrer chromosomalen Endstücke, der Telomere (Hayflick- Limit). Eine wesentliche Eigenschaft maligner Zellen ist die Immortalität. Der wahrscheinlich häufigste Mechanismus, durch den Tumorzellen eine scheinbar unbegrenzte Teilungsfähigkeit erlangen, ist die Aktivierung des Enzyms Telomerase, einer reversen Transkriptase, die den Verlust der Telomere rückgängig machen kann. Telomeraseaktivität konnten wir mit einem PCR-basierten TRAP-Assay in Tumorgewebsbiopsien, Ergussflüssigkeiten und Bronchiallavagen bei verschiedensten thorakalen Malignomen nachweisen.
Bei 47 Patienten mit Verdacht auf ein peripheres Bronchialkarzinom bestätigte sich durch spätere Operation oder invasive Diagnostik in 38 Fällen ein Malignom. Bei 25 von diesen 38 Patienten (66 %) war präoperativ in durchleuchtungsgestützten, bronchoskopischen Bürstenbiopsien Telomeraseaktivität nachweisbar gewesen. Es gab einen falsch positiven Fall (Tuberkulose). Mit einer Ausnahme waren die gleichzeitig entnommenen Bürstenbiopsien der Gegenseite negativ. In 23 Fällen (61 %) konnten zytologisch Tumorzellen gefunden werden. Bei 33 Patienten war mindestens ein Wert positiv. Die Kombination von Zytologie und Telomerasetest in Bürstenbiopsien erreichte damit eine diagnostische Sensitivität von 87 %.
Telomerase in Lung Cancer. Testing the Activity of the “Immortality Enzyme” in Bronchial Brush Biopsies Increases the Diagnostic Yield in Cases of Suspected Peripheral Bronchogenic Carcinomas:
The proliferative capability is time-limited in normal somatic cells by the shortening of their chromosomal ends, the telomeres (Hayflick limit). An important feature of malignant cells is their immortality. The probably most common mechanism of tumour cells to achieve unlimited replicability is the activation of the enzyme telomerase. The reverse transcriptase can compensate the loss of telomeres. Using a PCR-based TRAP assay we found telomerase activity in tumour biopsies, exsudates and bronchial washings in various thoracic malignancies.
In 38 of 47 patients with suspected peripheral lung cancer eventually surgery or invasive procedures proved a malignancy. In fluoroscopically guided bronchial brushings from 25 of these 38 patients (66 %) the TRAP assay revealed telomerase activity. There was a single false positive case (tuberculosis) and with a single exception, the simultaneously taken brushes of the contralateral lobes were all telomerase negative. In 23 patients (61 %) tumour cells were found in the cytological examination. In 33 patients at least one marker was positive. Thus the combination of cytology and telomerase test in bronchial brush biopsies attained a diagnostic yield of 87 %.
1 Herrn PD Dr. H.-N. Macha zum 60. Geburtstag gewidmet
2 Diese Studie wurde finanziert durch den Förderverein der Lungenklinik Hemer e.V.
Literatur
- 1 Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965; 37 614-634
- 2 Stanulis-Praeger B. Cellular senescence revisited: A review. Mech Ageing Develop. 1987; 18 1-48
- 3 Watson J D. Origin of concatemeric T7 DNA. Nat New Biol. 1972; 239 197-201
- 4 Harley C B, Futcher A B, Greider C W. Telomeres shorten during aging of human fibroblasts. Nature. 1990; 345 458-460
- 5 Harley C B, Vaziri H, Counter C M, Allsopp R C. The telomere hypothesis of cellular aging. Exp Gerontol. 1992; 27 375-382
- 6 Greider C W, Blackburn E H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature. 1989; 337 331-337
- 7 Oulton R, Harrington L. Telomeres, telomerase, and cancer: life on the edge of genomic stability. Current Opinion in Oncology. 2000; 12 74-81
- 8 Fossel M. Das Unsterblichkeitsenzym. Piper Verlag, München 1996
- 9 Yamaguchi F, Morrison R S, Takahashi H, Teramoto A. Anti-telomerase therapy suppressed glioma proliferation. Oncol Rep. 1999; 6 773-776
- 10 Sarvesvaran J, Going J J, Milroy R, Kaye S B, Keith W N. Is small cell lung cancer the perfect target for anti-telomerase treatment?. Carcinogenesis. 1999; 2 1649-1651
- 11 Hahn W C, Stewart S A, Brooks M W, York S G, Eaton E, Kurachi A, Beijersbergen R L, Knoll J H, Meyerson M, Weinberg R A. Inhibition of telomerase limits the growth of human cancer cells. Nat Med. 1999; 5 (10) 1164-70
- 12 Albanell J, Lonardo F, Rusch V, Engelhardt M, Langenfeld J, Han W, Klimstra D, Venkatraman E, Moore M A, Dmitrovsky E. High telomerase activity in primary lung cancer: association with increased cell proliferation rates and advanced pathological stage. J Nat Cancer Inst. 1997; 5, 89 1609-1615
- 13 Chin L, Artandi S E, Shen Q, Tam A, Lee S L, Gottlieb G J, Greider C W, DePinho R A. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999; 97 527
- 14 Bacchetti S, Counter C M. Telomeres and telomerase in human cancer. Int J Oncol. 1995; 7 423-432
- 15 Kim N W, Piatyszek M A, Prowse K R, Harley C B, West M D, Ho P L. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266 2011-2015
- 16 Shay J W, Bacchetti S. A survey of telomerase activity in human cancer. Europ J Cancer. 1997; 3 787-791
- 17 Hiyama K, Hiyama E, Ishioka S, Yamakido M, Inai K, Gazdar A F, Piatyszek M A, Shay J W. Telomerase activity in small-cell and non-small-cell lung cancers. J Nat Cancer Inst. 1995; 87 (12) 895-902
- 18 Marchetti A, Bertacca G, Buttitta F, Chella A, Quattrocolo G, Angeletti C A, Bevilacqua G. Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Cin Cancer Res. 1999; 8 2077-2081
- 19 Taga S, Osaki T, Ohgami A, Imoto H, Yasumoto K. Prognostic impact of telomerase activity in non-small cell lung cancers. Ann Surg. 1999; 23 715-720
- 20 Califano J, Ahrendt S A, Meininger G, Westra W H, Koch W M, Sidransky D. Detection of telomerase activity in oral rinses from head and neck squamous cell carcinoma patients. Cancer Res. 1996; 56 (24) 5720-5722
- 21 Hiyama K, Ishioka S, Shay J W, Taooka Y, Maeda A, Isobe T, Hiyama E, Maeda H, Yamakido M. Telomerase activity as a novel marker of lung cancer and immune-associated lung diseases. Int J Mol Med. 1998; Mar;1(3) 545-549
- 22 Arai T, Yasuda Y, Takaya T, Ito Y, Hayakawa K, Toshima S, Shibuya C, Yoshimi N, Kashiki Y. Application of telomerase activity for screening of primary lung cancer in broncho-alveolar lavage fluid. Oncol Rep. 1998; 5 (2) 405-408
- 23 Yahata N, Ohyashiki K, Ohyashiki J H, Iwama H, Hayashi S, Ando K, Hirano T, Tsuchida T, Kato H, Shay J W, Toyama K. Telomerase activity in lung cancer cells obtained from bronchial washings. J Natl Cancer Inst. 1998; 9 (90) 684-690
- 24 Xinarianos G, Scott F M, Liloglou T, Prime W, Turnbull L, Walshaw M, Field J K. Evaluation of telomerase activity in bronchial lavage as a potential diagnostic marker for malignant lung disease. Lung Cancer. 2000; 28 (1) 37-42
- 25 Ahrend S A, Chow J T, Xu L H. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst. 1999; 91 332
- 26 Yashima K, Litzky L A, Kaiser L, Rogers T, Lam S, Wistuba I I, Milchgrub S, Srivastava S, Piatyszek M A, Shay J W, Gazdar A F. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res. 1997; 57 (12) 2373-2377
- 27 Norrback K F, Dahlenborg K, Carlsson R, Roos G. Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas. Blood. 1996; 88 (1) 222-9
- 28 Engelhardt K, Kumar R, Albanell J, Pettengell R, Han W, Moore M A. Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells. Blood. 1997; 9 (1) 182-93
- 29 Ahrendt S A, Yang S C, Wu L, Westra W H, Jen J, Califano J A, Sidransky D. Comparison of oncogene mutation detection and telomerase activity for the molecular staging of non-small cell lung cancer. Clin Cancer Res. 1997; 3 (7) 1207-14
- 30 Yang C T, Lee M H, Lan R S, Chen J K. Telomerase activity in pleural effusions: diagnostic significance. J Clin Oncol. 1998; 16 (2) 567-573
- 31 Yang C T, Lin M C, Huang C C, Chen N H, Chen J K. Tuberculin purified derivative up-regulates the telomerase activity of peripheral blood mononuclear cells from patients with pulmonary tuberculosis. Life Sci. 1999; 64 (16) 1383-1391
- 32 Reddel R R, Bryan T M, Murnane J P. Immortalized cells with no detectable telomerase activity. Biochemistry. 1997; 62 1254-1262
- 33 Piatyszek M A, Kim N W, Weinrich S L, Hiyama K, Hiyama E, Wright W E. Detection of telomerase activity in human cells and tumors by a telomeric repeat amplification protocol (TRAP). Methods Cell Sci. 1995; 17 1-15
- 34 Cuthbert A P, Bond J, Trott D A, Gill S, Broni J, Marriott A. Telomerase repressor sequences on chromosome 3 and induction of permanent growth arrest in human breast cancer cells. J Nat Cancer Inst. 1999; 91 37-45
1 Herrn PD Dr. H.-N. Macha zum 60. Geburtstag gewidmet
2 Diese Studie wurde finanziert durch den Förderverein der Lungenklinik Hemer e.V.
PD Dr L Freitag
Lungenklinik Hemer
Theo-Funccius-Str. 1 58675 Hemer
Email: E-mail: lutzfrei@home.centernet.de