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Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.

Jin, Yuesheng LU ; Stewénius, Ylva LU ; Lindgren, David LU ; Frigyesi, Attila LU ; Calcagnile, Olga LU ; Jonson, Tord LU ; Edqvist, Anna LU ; Larsson, Nina LU ; Lundberg, Lena-Maria LU and Chebil, Gunilla, et al. (2007) In Clinical Cancer Research 13(6). p.1703-1712
Abstract
Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell... (More)
Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes. (Less)
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Clinical Cancer Research
volume
13
issue
6
pages
1703 - 1712
publisher
American Association for Cancer Research
external identifiers
  • wos:000245031800014
  • scopus:34250222085
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-06-2705
language
English
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yes
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38219d3c-5c3a-416e-8bec-e6e7ea822093 (old id 166506)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17363523&dopt=Abstract
date added to LUP
2007-07-07 09:02:22
date last changed
2017-02-22 11:44:08
@article{38219d3c-5c3a-416e-8bec-e6e7ea822093,
  abstract     = {Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.},
  author       = {Jin, Yuesheng and Stewénius, Ylva and Lindgren, David and Frigyesi, Attila and Calcagnile, Olga and Jonson, Tord and Edqvist, Anna and Larsson, Nina and Lundberg, Lena-Maria and Chebil, Gunilla and Liedberg, Fredrik and Gudjonsson, Sigurdur and Månsson, Wiking and Höglund, Mattias and Gisselsson Nord, David},
  issn         = {1078-0432},
  language     = {eng},
  number       = {6},
  pages        = {1703--1712},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-06-2705},
  volume       = {13},
  year         = {2007},
}