Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells

Many cancer cells display a CIN (Chromosome Instability) phenotype, by which they exhibit high rates of chromosome loss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesis failure, and merotelic kinetochore orientation, h...

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Published in:	PloS one Vol. 4; no. 8; p. e6564
Main Authors:	Silkworth, William T, Nardi, Isaac K, Scholl, Lindsey M, Cimini, Daniela
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 10-08-2009 Public Library of Science (PLoS)
Subjects:	Accessories Analysis Anaphase Apoptosis Biomedical research Cancer Cancer cells Cancer genetics Cell Biology Cell Biology/Cell Growth and Division Cell Biology/Cytoskeleton Cell cycle Cell Line, Tumor Cell Polarity Chromosomal Instability Chromosomes Coalescence Coalescing Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Cytokinesis Defects Error correction & detection Genetic aspects Genomes Humans Kinases Kinetochores Metaphase Microscopy, Confocal Mitosis Spindle Apparatus Spindles Stability Studies Tubulin Tumorigenesis United States > US Virginia
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Summary:	Many cancer cells display a CIN (Chromosome Instability) phenotype, by which they exhibit high rates of chromosome loss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesis failure, and merotelic kinetochore orientation, have been proposed as causes of CIN. However, a comprehensive theory of how CIN is perpetuated is still lacking. We used CIN colorectal cancer cells as a model system to investigate the possible cellular mechanism(s) underlying CIN. We found that CIN cells frequently assembled multipolar spindles in early mitosis. However, multipolar anaphase cells were very rare, and live-cell experiments showed that almost all CIN cells divided in a bipolar fashion. Moreover, fixed-cell analysis showed high frequencies of merotelically attached lagging chromosomes in bipolar anaphase CIN cells, and higher frequencies of merotelic attachments in multipolar vs. bipolar prometaphases. Finally, we found that multipolar CIN prometaphases typically possessed gamma-tubulin at all spindle poles, and that a significant fraction of bipolar metaphase/early anaphase CIN cells possessed more than one centrosome at a single spindle pole. Taken together, our data suggest a model by which merotelic kinetochore attachments can easily be established in multipolar prometaphases. Most of these multipolar prometaphase cells would then bi-polarize before anaphase onset, and the residual merotelic attachments would produce chromosome mis-segregation due to anaphase lagging chromosomes. We propose this spindle pole coalescence mechanism as a major contributor to chromosome instability in cancer cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Conceived and designed the experiments: WTS IKN DC. Performed the experiments: WTS IKN LMS. Analyzed the data: WTS IKN LMS DC. Contributed reagents/materials/analysis tools: DC. Wrote the paper: WTS DC.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0006564