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Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis
Yvonne Begus-Nahrmann, … , André Lechel, K. Lenhard Rudolph
Yvonne Begus-Nahrmann, … , André Lechel, K. Lenhard Rudolph
Published May 24, 2012
Citation Information: J Clin Invest. ;122(6):2283-2288. https://doi.org/10.1172/JCI61745.
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Brief Report

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

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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.

Authors

Yvonne Begus-Nahrmann, Daniel Hartmann, Johann Kraus, Parisa Eshraghi, Annika Scheffold, Melanie Grieb, Volker Rasche, Peter Schirmacher, Han-Wong Lee, Hans A. Kestler, André Lechel, K. Lenhard Rudolph

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Figure 1

Transient telomere dysfunction promotes hepatocarcinogenesis.

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Transient telomere dysfunction promotes hepatocarcinogenesis.
Mice were ...
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). (F–H) 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.
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