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. 2012 Jun;122(6):2283-8.
doi: 10.1172/JCI61745. Epub 2012 May 24.

Transient Telomere Dysfunction Induces Chromosomal Instability and Promotes Carcinogenesis

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Transient Telomere Dysfunction Induces Chromosomal Instability and Promotes Carcinogenesis

Yvonne Begus-Nahrmann et al. J Clin Invest. .
Free PMC article

Abstract

Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.

Figures

Figure 1
Figure 1. Transient telomere dysfunction promotes hepatocarcinogenesis.
Mice were treated with the liver carcinogen DEN at P15. Transient telomere dysfunction was induced by doxycycline-inducible TRF2ΔBΔM expression in TTD+ but not in TTD mice. (A and B) The incidence of dysplastic foci (A) and macroscopic liver tumors (B) in 6-month-old TTD+ male mice (n = 7) was significantly increased compared with that in age-matched TTD male mice (n = 18). (C and D) Analysis of foci (C) and tumors (D) in 13-month-old TTD+, TTD, and G3 mTerc–/– female mice (n = 19, n = 20, and n = 17, respectively). (E) The scatter plot shows the distribution of tumor size from all tumors analyzed in 13-month-old male mice on a logarithmic scale. Tumor volume was significantly increased in TTD+ (n = 136) compared with TDD mice (n = 233) and G3 mTerc–/– mice (n = 302). (FH) Transient telomere dysfunction was induced after establishment of macroscopic HCCs in tumors of 12- to 14-month-old female mice. MRI imaging determined the tumor volume before and 1 month after induction of telomere dysfunction. (F) Transient telomere dysfunction in TTD+ mice led to a significant increase in tumor size (n = 31) compared with the control groups (n = 60; P = 0.0002). Dox, doxycycline. (G) Representative MRI images of TTD+ and TTD mice before and after doxycycline treatment (circles highlight detected tumors). (H) Tumor volumes of both groups prior to doxycycline treatment. Data represent mean ± SEM.
Figure 2
Figure 2. Transient telomere dysfunction induces HCCs with shortened telomeres.
Telomere length was measured by qFISH. (AC) Distribution of mean telomere fluorescence intensities (TFI) in HCCs of the indicated genotypes and sex (n = 5–7). Red lines indicate the mean fluorescence intensities. The numbers on the left of the dotted line indicate the percentage of tumor cells with critically short telomeres (TFI < 800).
Figure 3
Figure 3. Transient telomere dysfunction induces chromosomal instability in telomerase-proficient liver without strong accumulation of DNA damage.
(A) Ideogram displaying chromosomal gains and losses in tumors of the indicated cohorts (n = 6–10). The bars on the right side of each chromosome indicate the frequency (%) of gains (red) and losses (green). (B) Average number of chromosomal alterations in HCCs of the indicated genotypes (n = 6–10). (C) The histogram shows the number of γH2AX-positive cells in HCCs of the indicated genotypes (n = 5–9). (D) Representative immunofluorescence staining of γH2AX foci as an indicator of DNA breaks. Original magnification, ×200. (E) Number of PCNA-positive cells in nontumorous livers and HCCs of mice of the indicated genotypes (n = 5–9). Data represent mean ± SEM.

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