Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse

Greenberg, Roger A.; Chin, Lynda; Femino, Andrea M.; Lee, Kee-Ho; Gottlieb, Geoffrey J.; Singer, Robert H.; Greider, Carol W.; DePinho, Ronald A.

doi:10.1016/s0092-8674(00)80761-8

Cited by 354 publications

(253 citation statements)

References 55 publications

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“…Studies using knockout mice have demonstrated that depending on the cell type and genomic context, telomeres may exert dual and even opposite effects in cancer, on one side limiting tumor growth, while on the other side promoting tumorigenesis. 30,31 It has been hypothesized that longer telomeres and especially telomerase activation, leading to longer cellular survival and, therefore, the accumulation of genetic mutations might be the cause of an increased cancer risk incidence with longer TL. 32,33 Moreover, based on animal and in vitro studies, it seems that an early activation of telomerase via exogenous regulators of human telomerase reverse transcriptase, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies.…”

Section: Discussionmentioning

confidence: 99%

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

et al. 2014

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Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B‐cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case–control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p = 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2–4, respectively, p‐trend = 0.001], diffuse large B‐cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2–4, respectively, p‐trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2–4, respectively, p‐trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.

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Section: Discussionmentioning

confidence: 99%

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

et al. 2014

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“…Both in vitro and in vivo, overexpression of telomerase in cancer cells appears to be crucial for tumor progression (Greenberg et al, 1999;Hahn et al, 1999a, b;Gonzalez-Suarez et al, 2000Elenbaas et al, 2001;Artandi et al, 2002). On the other hand, studies on mice lacking the telomerase RNA gene demonstrate that critical telomere shortening and telomere instability can favor initial stages of cancer formation and cooperates with p53 deficiency to favor carcinogenesis Rudolph et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to cradiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

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“…This model has led some to propose that telomerase inhibition may be an effective anti-neoplastic strategy (Counter et al 1992). In support of this model, mice lacking both mTERC and p16 INK4A show a reduced incidence of tumor formation compared with mice lacking p16 INK4A alone (Greenberg et al 1999). This experiment suggests that in certain genetic backgrounds, telomere dysfunction can impair tumorigenesis.…”

Section: Barriers To Immortalization: Crisismentioning

confidence: 95%

Immortalized cells as experimental models to study cancer

Boehm

Hahn

2004

Cytotechnology

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The development of cancer is a multi-step process in which normal cells sustain a series of genetic alterations that together program the malignant phenotype. Much of our knowledge of cancer biology results from the detailed study of specimens and cell lines derived from patient tumors. While these approaches continue to yield critical information regarding the identity, number, and types of alterations found in human tumors, further progress in understanding the molecular basis of malignant transformation depends upon the generation and use of increasingly sophisticated experimental models of cancer. Over the past several years, the recognition that telomeres and telomerase play essential roles in regulating cell lifespan now permits the development of new models of human cancer. Here we review recent progress in the use of immortalized human cells as a foundation for understanding the molecular basis of cancer.Abbreviations: ALT -alternative lengthening of telomeres; HEK -human embryonic kidney; HMEChuman mammary epithelial cell; HPV -human papillomavirus; hTERT -human telomerase reverse transcriptase; LT -SV40 Large T antigen; PD -population doubling; PP2A -protein phosphatase 2A; RalGEF -Ral guanine nucleotide exchange factor; RAS -activated H-Ras allele; shRNA -short hairpin RNA; ST -SV40 small t antigen; TRF -telomere restriction fragment.

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Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse

Cited by 354 publications

References 55 publications

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

Immortalized cells as experimental models to study cancer

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