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Telomere dysfunction and evolution of intestinal carcinoma in mice and humans

Nature Genetics volume 28, pages 155–159 (2001)Cite this article

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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Figure 1: Telomere shortening has contrasting effects on the survival of ApcMin mice.
Figure 2: Contrasting effects of telomere shortening on tumor formation in ApcMin mice.
Figure 3: Telomere shortening inhibits progression of intestinal neoplasia.
Figure 4: Degree of telomere dysfunction affects adenoma progression.
Figure 5: Telomere dysfunction peaks at the adenoma-carcinoma transition in human colorectal carcinogenesis.

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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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Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Karl Lenhard Rudolph, Melissa Millard, Marcus W. Bosenberg & Ronald A. DePinho

  2. Department of Pathology, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Marcus W. Bosenberg

  3. Departments of Medicine and Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ronald A. DePinho

  4. Department of Gastroenterology and Hepatology, Medical School Hannover, Hannover, 30623, Germany

    Karl Lenhard Rudolph

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Correspondence to Ronald A. DePinho.

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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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