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

Research output: Contribution to journalArticle

Standard

Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers. / Jin, Yuesheng; Stewénius, Ylva; Lindgren, David; Frigyesi, Attila; Calcagnile, Olga; Jonson, Tord; Edqvist, Anna; Larsson, Nina; Lundberg, Lena-Maria; Chebil, Gunilla; Liedberg, Fredrik; Gudjonsson, Sigurdur; Månsson, Wiking; Höglund, Mattias; Gisselsson Nord, David.

In: Clinical Cancer Research, Vol. 13, No. 6, 2007, p. 1703-1712.

Research output: Contribution to journalArticle

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.

AU - Jin, Yuesheng

AU - Stewénius, Ylva

AU - Lindgren, David

AU - Frigyesi, Attila

AU - Calcagnile, Olga

AU - Jonson, Tord

AU - Edqvist, Anna

AU - Larsson, Nina

AU - Lundberg, Lena-Maria

AU - Chebil, Gunilla

AU - Liedberg, Fredrik

AU - Gudjonsson, Sigurdur

AU - Månsson, Wiking

AU - Höglund, Mattias

AU - Gisselsson Nord, David

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Immunology (013212020), Cardiology (013230026), Pathology, (Lund) (013030000), Department of Urology, Lund (013077000), Division of Clinical Genetics (013022003), GABA Channels in Physiology and Pharmacology (013241570), Neurosurgery (013026000)

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-06-2705

DO - 10.1158/1078-0432.CCR-06-2705

M3 - Article

VL - 13

SP - 1703

EP - 1712

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -