Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis

Hackett, Jennifer A.; Greider, Carol W.

doi:10.1038/sj.onc.1205061

Cited by 222 publications

(172 citation statements)

References 59 publications

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“…[12][13][14][15][16] Telomere shortening has been suggested to be an important biological factor in aging, cellular senescence, cell immortality, and transformation to cancer; the last two are associated with reactivation of the enzyme telomerase in cells with critically shortened telomeres. 24 In the presence of shortened telomere repeat fragments, the ends of linear chromosomes may undergo so-called anomalous bridge-fusion-breakage events that result in both structural and numerical chromosomal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…10 Telomeric repeat sequences prevent fusion between ends of chromosomes, and telomeric dysfunction is a major mechanism for the generation of chromosomal instability (CIN). [11][12][13][14][15][16] Telomeric fusions between chromosomal arms may occur in the presence of critically shortened telomere repeat sequences; such fusions lead to ring and dicentric chromosomes that form socalled anaphase bridges during mitosis. 15 Breakage of anaphase bridges generates highly recombinogenic free DNA ends, with fusion of broken ends resulting in novel chromosomal rearrangements.…”

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confidence: 99%

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Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Heek

Meeker

Kern

et al. 2002

The American Journal of Pathology

321

213

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A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently de- The 5-year survival rate of patients with ductal adenocarcinoma of the pancreas is 4%, one of the lowest of any neoplasm. Each year, nearly 29,000 patients are diagnosed with pancreatic cancer in the United States, and almost all will succumb to their disease.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Heek

Meeker

Kern

et al. 2002

The American Journal of Pathology

321

213

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“…Interestingly, telomeres form protective caps on chromosome ends for genomic integrity and stability that are important for continuous proliferation including cancer [7,8]. Owing to the 'end replication problem', telomeres shorten progressively with each round of cell division, and subsequently, cells are triggered to enter a permanent growth arrest stage named 'replicative senescence' when their telomeres reach a critical size that elicits the DNA damage checkpoint response or p53 and Rb activation [8,9].…”

Section: Telomeres and Telomerasementioning

confidence: 99%

TGF-β and cancer: Is Smad3 a repressor of hTERT gene?

Toh

et al. 2006

Cell Res

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“…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.…”

mentioning

confidence: 99%

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

et al. 2006

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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.

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Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis

Cited by 222 publications

References 59 publications

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

TGF-β and cancer: Is Smad3 a repressor of hTERT gene?

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

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