TY - JOUR
T1 - Telomere dysfunction and evolution of intestinal carcinoma in mice and humans
AU - Rudolph, Karl Lenhard
AU - Millard, Melissa
AU - Bosenberg, Marcus W.
AU - DePinho, Ronald A.
N1 - Funding Information:
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.
PY - 2001
Y1 - 2001
N2 - Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. 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-/- mice, 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 instability. 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.
AB - Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. 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-/- mice, 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 instability. 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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U2 - 10.1038/88871
DO - 10.1038/88871
M3 - Article
C2 - 11381263
AN - SCOPUS:0034978564
SN - 1061-4036
VL - 28
SP - 155
EP - 159
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -