Abstract
Telomerase activation is a common feature of advanced human cancers1 and facilitates the malignant transformation of cultured human cells2 and in mice3,4. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis5,6,7. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice8 has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis9. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc−/− mice10,11, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability12,13,14,15. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.
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Acknowledgements
We thank D. Castrillon and S. Chang for helpful advice regarding the pathological and histological classification of intestinal neoplasia; L. Chin, S. Weiler and R. Greenberg for critical review of the manuscript; and P. Flemming and M. Manns for access to the histology archives of the Medical School Hannover. K.L.R. was supported by Deutsche Forschungsgemeinschaft grant Ru 745/1-1, M.W.B. is supported by a Howard Hughes Medical Institute Physician Postdoctoral fellowship and the work was supported by National Institutes of Health grants to R.A.D., who is an American Cancer Society Research Professor and a Kirsch Foundation Scholar.
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Rudolph, K., Millard, M., Bosenberg, M. et al. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 28, 155–159 (2001). https://doi.org/10.1038/88871
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DOI: https://doi.org/10.1038/88871
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