Biology Reference
In-Depth Information
correlates with aneuploidy, defined as a state of cells with abnormal numbers of
chromosomes, as well as with chromosomal instability (CIN), which describes the rate
of chromosome gains and losses as well as structural chromosome aberrations in cell
populations, and malignant behavior in tumor cell lines, mouse tumor models, and
human tumors (Nigg
2002
;Lingleetal.
1998
; Neben et al.
2003
; Krämer et al.
2003
;
Koutsami et al.
2006
; Levine et al.
1991
; Pihan et al.
2001
)
CIN is a feature commonly observed in human cancers and was first identified
almost a century ago (von Hansemann
1890
). Only recently, using elaborate
mouse models, it became clear that CIN does not only correlate with but probably
plays a causative part in a substantial proportion of malignancies (Weaver et al.
2007
; Sotillo et al.
2007
; Baker et al.
2009
). One major cause of CIN is mitotic
checkpoint overactivation (Schvartzman et al.
2010
). Here, we focus on recent
discoveries related to another phenomenon intricately linked to CIN, centrosomal
clustering, its emerging mechanistic basis, significance for cancer cell survival,
tumor progression, role in asymmetric divisions of stem cells, and as a potential
tumor-selective therapeutic target.
17.2 Centrosome Clustering and Chromosomal Instability
In mitosis, supernumerary centrosomes can form multipolar spindles, which occur
in many tumor types and have long been accused of contributing to CIN and
tumorigenesis (Nigg
2002
; Krämer et al.
2002
; Boveri
1929
). However, recent
findings show that multipolar divisions and the resulting CIN undermine cell
viability, frequently leading to cell death (Weaver et al.
2007
; Ganem et al.
2009
;
Brinkley
2001
; Kops et al.
2004
). To avoid cell death, many cancer cells cluster
supernumerary centrosomes into two spindle poles thereby enabling bipolar
division. The earliest observation on centrosomal clustering came from immu-
nofluorescence studies of N115 mouse neuroblastoma cells which contain large
numbers of centrioles, and yet undergo mostly bipolar divisions, with often
unequal numbers of centrioles coalescing at the two spindle poles (Ring et al.
1982
). Forgotten for many years, Salisbury and colleagues rediscovered the phe-
nomenon after having noted the low frequency of abnormal mitoses despite the
presence of supernumerary centrosomes in human breast cancer samples (Lingle
and Salisbury
1999
). Whether or not centrosomal clustering was coupled with
reduced CIN was not examined at that time. Indeed, the concept that has crys-
tallized since these pioneering studies is that centrosomal clustering enables cells
to successfully divide despite the presence of supernumerary centrosomes (Nigg
2002
; Brinkley
2001
).
The initial description of centrosome clustering noted that cells with supernumerary
centrosomes pass through a transient multipolar spindle intermediate before centro-
some clustering and bipolar anaphase occurs (Ring et al.
1982
). Excitingly, recent data
from several laboratories demonstrate that, while passing through the transient mul-
tipolar state, merotelic kinetochore MT attachment errors, defined by the persistent
