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The telomere in cancer
EDITORIAL The Telomere in Cancer All's Not Well That Doesn't End Well
In 1938 Hermann J. Muller created the concept of the telomere [1] and coined the word from the Greek telos for " e n d " and meros for "part." Although the telomere was morphologically unremarkable, its uniqueness stemmed from its behavior. The telomere protected the end of the chromosome from foreign and domestic entanglements. Telomere loss led to an unstable chromosome that could participate in endto-end fusion and ring c h r o m o s o m e formation. Healing of the end of a c h r o m o s o m e could occur, albeit rarely. This indicated that the telomere was not an i m m u t a b l e object but rather the product of a d y n a m i c process. The telomere also had to permit the end of the c h r o m o s o m e to replicate and divide along with the rest of the chromosome during the cell cycle. Pertinent observations were reported by Bernard Dutrillaux and his colleagues in 1977 [2]. Many cells from a patient with the Thiberge-Weissenbach s y n d r o m e (an association of telangiectasia, calcinosis and scleroderma) showed end-to-end chromosome fusion resulting in multicentric rods and gigantic rings. The fused c h r o m o s o m e s were random. Today we w o u l d w o n d e r whether the patient had a telomerase deficiency. Telomeric DNA consists of t a n d e m repeats of short simple sequences of bases oriented 5' --~ 3' toward the c h r o m o s o m e end. The telomere is lengthened by the action of the enzyme telomerase, w h i c h adds more repeats to the 3' end, and shortened by the action of DNA primase during DNA synthesis in the cell cycle [3]. Somatic cells that are dividing m a n y times, as in aging and cancer, appear to suffer progressive shortening of the telomere [4], consistent with the inactivity of telomerase in somatic cells. Healing of the end of chromosome 16 by the a d d i t i o n of the h u m a n telomeric report TTAGGG has been reported [5]. The " n e w " telomere was heritable. Cancer cells live life in the fast lane and can use up their allotted lengths of telomeres with abandon. The consequences of this autocannibalism can be grave, including chromosome rearrangement, bridge-breakage-fusion cycles, and the generation of d u p l i c a t i o n and deletion chromosomes, all being characteristic of cancer cells. Absence of telomeric sequences can occur in cancer. This has been found with double-minute chromosomes in h u m a n colon carcinoma [6]. Because double minutes lack a kinetochore [7], they should not even be considered as c h r o m o s o m e s but rather as mere pieces of chromatin. What roles in cancer are played by telomere changes? Three roles can be visualized. Telomere changes may initiate cancer. Telomere changes may promote cancer progression. A n d telomere changes m a y occur as the consequence of cancer treatment. These possibilities are not m u t u a l l y exclusive. We w o u l d think that at least two of these roles will be proven. The telomere is here ta stay in cancer research. One matter that remains to be settled is whether telomere changes can be prevented. Are there ways to maintain the stability and integrity of the telomere? Another matter that still has to be settled is whether, once shortened, can a telomere be lengthened. Can we put a telomere back on a chromosome?
245 © 1991 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 54:245 246 (1991)
0165-4608/91/$03.50
246
F. Hecht
William Shakespeare wrote a play called " A l l ' s Well that Ends W el l " [8]. His title was used for an essay on telomeres in Nature [3]. With telomere shortening and loss in cancer, however, it might be feared that " A l i ' s not well that doesn't end w e l l . " FREDERICK HECHT BARBARA K. HECHT
Molecular Medicine and Genetics The Children's Mercy Hospital 2401 Gillham Kansas City, MO 64108
REFERENCES 1. Muller HJ (1938): The remaking of chromosomes. Collecting Net, Woods Hole 13:181-195; 13:198. 2. Dutrillaux B, Aurias A, Couturier J, Croquette MF, Vieges-Pequignot C (1977): Multiple telomeric fusions and chain configurations in human somatic chromosomes. Chromosomes Today 6:37-44. 3. Murray A (1990): Telomeres: Ali's well that ends well. Nature 346:797-798. 4. Wilkie AOM, Lamb J, Harris PC, Finney RD, Higgs DR (1990): A truncated human chromosome 16 associated with a thalassaemia is stabilized by addition of telomeric repeat (TTAGGG). Nature 346:868-871. 5. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RD (1990): Telomere reduction in human colorectal carcinoma and with aging. Nature 346:866-868. 6. Lin CC, Meyne J, Sasi R, Moyzis RK (1990). Apparent lack of telomere sequences on double minute chromosomes. Cancer Genet Cytogenet 48:271-274. 7, Haaf T, Schmid M (1988): Analysis of double minutes and double minute-like chromatin in human and murine cells using anti-kinetochore antibodies. Cancer Genet Cytogenet 30:73-82. 8. Shakespeare W (1602]: Ali's Well that Ends Well. London.
In 1938 Hermann J. Muller created the concept of the telomere [1] and coined the word from the Greek telos for " e n d " and meros for "part." Although the telomere was morphologically unremarkable, its uniqueness stemmed from its behavior. The telomere protected the end of the chromosome from foreign and domestic entanglements. Telomere loss led to an unstable chromosome that could participate in endto-end fusion and ring c h r o m o s o m e formation. Healing of the end of a c h r o m o s o m e could occur, albeit rarely. This indicated that the telomere was not an i m m u t a b l e object but rather the product of a d y n a m i c process. The telomere also had to permit the end of the c h r o m o s o m e to replicate and divide along with the rest of the chromosome during the cell cycle. Pertinent observations were reported by Bernard Dutrillaux and his colleagues in 1977 [2]. Many cells from a patient with the Thiberge-Weissenbach s y n d r o m e (an association of telangiectasia, calcinosis and scleroderma) showed end-to-end chromosome fusion resulting in multicentric rods and gigantic rings. The fused c h r o m o s o m e s were random. Today we w o u l d w o n d e r whether the patient had a telomerase deficiency. Telomeric DNA consists of t a n d e m repeats of short simple sequences of bases oriented 5' --~ 3' toward the c h r o m o s o m e end. The telomere is lengthened by the action of the enzyme telomerase, w h i c h adds more repeats to the 3' end, and shortened by the action of DNA primase during DNA synthesis in the cell cycle [3]. Somatic cells that are dividing m a n y times, as in aging and cancer, appear to suffer progressive shortening of the telomere [4], consistent with the inactivity of telomerase in somatic cells. Healing of the end of chromosome 16 by the a d d i t i o n of the h u m a n telomeric report TTAGGG has been reported [5]. The " n e w " telomere was heritable. Cancer cells live life in the fast lane and can use up their allotted lengths of telomeres with abandon. The consequences of this autocannibalism can be grave, including chromosome rearrangement, bridge-breakage-fusion cycles, and the generation of d u p l i c a t i o n and deletion chromosomes, all being characteristic of cancer cells. Absence of telomeric sequences can occur in cancer. This has been found with double-minute chromosomes in h u m a n colon carcinoma [6]. Because double minutes lack a kinetochore [7], they should not even be considered as c h r o m o s o m e s but rather as mere pieces of chromatin. What roles in cancer are played by telomere changes? Three roles can be visualized. Telomere changes may initiate cancer. Telomere changes may promote cancer progression. A n d telomere changes m a y occur as the consequence of cancer treatment. These possibilities are not m u t u a l l y exclusive. We w o u l d think that at least two of these roles will be proven. The telomere is here ta stay in cancer research. One matter that remains to be settled is whether telomere changes can be prevented. Are there ways to maintain the stability and integrity of the telomere? Another matter that still has to be settled is whether, once shortened, can a telomere be lengthened. Can we put a telomere back on a chromosome?
245 © 1991 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 54:245 246 (1991)
0165-4608/91/$03.50
246
F. Hecht
William Shakespeare wrote a play called " A l l ' s Well that Ends W el l " [8]. His title was used for an essay on telomeres in Nature [3]. With telomere shortening and loss in cancer, however, it might be feared that " A l i ' s not well that doesn't end w e l l . " FREDERICK HECHT BARBARA K. HECHT
Molecular Medicine and Genetics The Children's Mercy Hospital 2401 Gillham Kansas City, MO 64108
REFERENCES 1. Muller HJ (1938): The remaking of chromosomes. Collecting Net, Woods Hole 13:181-195; 13:198. 2. Dutrillaux B, Aurias A, Couturier J, Croquette MF, Vieges-Pequignot C (1977): Multiple telomeric fusions and chain configurations in human somatic chromosomes. Chromosomes Today 6:37-44. 3. Murray A (1990): Telomeres: Ali's well that ends well. Nature 346:797-798. 4. Wilkie AOM, Lamb J, Harris PC, Finney RD, Higgs DR (1990): A truncated human chromosome 16 associated with a thalassaemia is stabilized by addition of telomeric repeat (TTAGGG). Nature 346:868-871. 5. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RD (1990): Telomere reduction in human colorectal carcinoma and with aging. Nature 346:866-868. 6. Lin CC, Meyne J, Sasi R, Moyzis RK (1990). Apparent lack of telomere sequences on double minute chromosomes. Cancer Genet Cytogenet 48:271-274. 7, Haaf T, Schmid M (1988): Analysis of double minutes and double minute-like chromatin in human and murine cells using anti-kinetochore antibodies. Cancer Genet Cytogenet 30:73-82. 8. Shakespeare W (1602]: Ali's Well that Ends Well. London.