Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines

Bryan, Tracy M.; Englezou, Anna; Dalla‐Pozza, Luciano; Dunham, Melissa A.; Reddel, Roger R.

doi:10.1038/nm1197-1271

Cited by 1,158 publications

(900 citation statements)

References 29 publications

Supporting

Mentioning

858

Contrasting

Unclassified

Order By: Relevance

“…lengthening telomeres pathway in a subset of biliary carcinomas. 37,38 An important corroborative finding in these experiments is the normal telomere length present in inflamed but otherwise normal gallbladder epithelium. As carcinomas of the gallbladder typically arise in a background of chronic inflammation with metaplasia, lack of telomere length changes in non-metaplastic specimens suggests that telomere shortening is specific for longstanding pre-neoplastic and neoplastic changes, rather than acute, reactive changes associated with increased cell turnover.…”

Section: Discussionmentioning

confidence: 53%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 53%

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

et al. 2006

View full text Add to dashboard Cite

show abstract

“…For cells containing M independent telomeres of lengths x = (x 1 ,…, x M ), the density of cells n(x, t) satisfies the M-dimensional convectiondiffusion-growth equation (4) with absorbing boundaries when any telomere length x i reaches 0. The solution simply factorizes as a product of one-dimensional solutions (5) If each telomere has initial length x 0 , all the c(x i , t) are the same and are given by (A.2). We can also straightforwardly study the case where each telomere has a different initial length by merely using the unique initial length of each telomere in Eq.…”

Section: Telomere Replication Modelmentioning

confidence: 99%

“…This latter mechanism, known as alternative lengthening of telomeres (ALT), as well as additional telomerase activity in some cases, are thought to contribute to the large proliferative potential of these cells [5]. Here proliferative potential denotes the time over which cells can continue to divide.…”

Section: Introductionmentioning

confidence: 99%

Aging and immortality in a cell proliferation model

Antal

Blagoev

Trugman

et al. 2007

Journal of Theoretical Biology

View full text Add to dashboard Cite

We investigate a model of cell division in which the length of telomeres within a cell regulates its proliferative potential. At each division, telomeres undergo a systematic length decrease as well as a superimposed fluctuation due to exchange of telomere DNA between the two daughter cells. A cell becomes senescent when one or more of its telomeres become shorter than a critical length. We map this telomere dynamics onto a biased branching diffusion process with an absorbing boundary condition whenever any telomere reaches the critical length. Using first-passage ideas, we find a phase transition between finite lifetime and immortality (infinite proliferation) of the cell population as a function of the influence of telomere shortening, fluctuations, and cell division.

show abstract

“…This observation raised the possibility that FEN1 depletion or mutation might affect telomere stability in transformed cells that utilized the alternative lengthening of telomere (ALT) mechanism of telomere maintenance. Thus, we investigated whether FEN1 depletion affected telomere stability in a human osteosarcoma cell line (U2OS) that is telomerase negative and maintains its telomeres through the recombination-dependent ALT mechanism (Bryan et al, 1997). To control for possible off-target effects associated with RNA interference, we utilized two independent lentiviral constructs expressing short hairpin RNAs targeted to FEN1's coding region and 3 0 untranslated region (shFEN and shFEN3, respectively).…”

mentioning

confidence: 99%

FEN1 contributes to telomere stability in ALT-positive tumor cells

Saharia

Stewart

2009

Oncogene

View full text Add to dashboard Cite

Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.

show abstract

Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines

Cited by 1,158 publications

References 29 publications

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

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

Aging and immortality in a cell proliferation model

FEN1 contributes to telomere stability in ALT-positive tumor cells

Contact Info

Product

Resources

About