“…16 In certain cells, such as germline embryonic cells, maintenance of telomere length occurs through the activity of the enzyme telomerase; [27][28][29] however, enzymatic activity is not detected in most adult somatic cells. Telomere shortening has been demonstrated to induce a variety of genetic changes, including chromosome fusion at sites of shortened telomeres and recombination events, both of which contribute to genomic instability.…”
Section: Discussionmentioning
confidence: 99%
“…33 The eventual outcome of telomere shortening includes such varied processes as apoptosis, cellular senescence, and genetic instability. 16 The outcome of telomere shortening is influenced by additional genetic alterations within cells. For example, proper function of p53 is required to promote either senescence or apoptosis within cells carrying shortened telomeres, thus preventing proliferation of cells at high risk for neoplastic transformation.…”
Section: Discussionmentioning
confidence: 99%
“…13,14 Telomeres consist of DNA-protein structures, which serve as 'caps' on the ends of linear chromosomes that allow cells to distinguish between double-stranded breaks in the DNA and normal chromosome ends. 15,16 In humans, telomeric DNA sequences consist of 1000-2000 tandem repeats of TTAGGG, which generally shorten following cell division owing to incomplete replication of telomere repeats during DNA synthesis (the 'end-replication problem'). Severe telomere shortening can result in degradation of proximal or internal DNA with subsequent loss of genetic information, recombination of DNA at these sites, or fusion of chromosomes containing shortened telomeres.…”
Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.
“…16 In certain cells, such as germline embryonic cells, maintenance of telomere length occurs through the activity of the enzyme telomerase; [27][28][29] however, enzymatic activity is not detected in most adult somatic cells. Telomere shortening has been demonstrated to induce a variety of genetic changes, including chromosome fusion at sites of shortened telomeres and recombination events, both of which contribute to genomic instability.…”
Section: Discussionmentioning
confidence: 99%
“…33 The eventual outcome of telomere shortening includes such varied processes as apoptosis, cellular senescence, and genetic instability. 16 The outcome of telomere shortening is influenced by additional genetic alterations within cells. For example, proper function of p53 is required to promote either senescence or apoptosis within cells carrying shortened telomeres, thus preventing proliferation of cells at high risk for neoplastic transformation.…”
Section: Discussionmentioning
confidence: 99%
“…13,14 Telomeres consist of DNA-protein structures, which serve as 'caps' on the ends of linear chromosomes that allow cells to distinguish between double-stranded breaks in the DNA and normal chromosome ends. 15,16 In humans, telomeric DNA sequences consist of 1000-2000 tandem repeats of TTAGGG, which generally shorten following cell division owing to incomplete replication of telomere repeats during DNA synthesis (the 'end-replication problem'). Severe telomere shortening can result in degradation of proximal or internal DNA with subsequent loss of genetic information, recombination of DNA at these sites, or fusion of chromosomes containing shortened telomeres.…”
Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.
“…We now know that this limit is due in large measure to the loss of telomeric DNA that occurs when cells that do not express telomerase undergo DNA replication (Levy et al, 1992;Wright and Shay, 2001). Telomeres, the DNA sequence and proteins that cap the ends of linear chromosomes, are essential chromosomal elements, loss of which causes genomic instability, an enormous risk factor for malignant transformation (Artandi and DePinho, 2000;Shay and Wright, 2001;Kim et al, 2002;Blasco, 2003). Thus, the senescence response to short dysfunctional telomeres serves to arrest the growth of cells in danger of genomic instability, consistent with its role in tumor suppression.…”
Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responsesapoptosis or senescence-that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation. We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropyprotecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms. # 2004 Published by Elsevier Ireland Ltd.
“…A critical shortening of telomeres, associated with each DNA replication in most normal somatic cells, leads to the cessation of cell division, a metabolic state called senescence (Kim et al, 2002). Telomeric dysfunction is associated with very short telomeres, induces cell 'crisis' with chromosomal instability, endto-end chromosome fusions, activation of DNA checkpoint responses, apoptosis and cell death (Blackburn, 2001;Kim et al, 2002).…”
Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 mM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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