Biology Reference
In-Depth Information
indicate that the tumour is genetically unstable. It was observed that in some
haematological cancers, malignant cells were stably aneuploid, following chro-
mosomal redistribution earlier during tumorigenesis. More often, though, aneu-
ploid cancer cells derive from an increase in the rate of gain or loss of whole
chromosomes, a condition known as chromosome instability (CIN) (Kops et al.
2005
; Lengauer et al.
1998
). Although aneuploidy has been often suggested as the
driving force behind tumorigenesis, the rate at which chromosomes are gained or
lost can cause different outcomes. While moderate levels of CIN facilitate tumour
formation and development, massive changes in chromosome content can be
intolerable to cancer cells (reviewed by Godinho et al.
2009
). A number of studies
have shown that high levels of chromosome missegregation and aneuploidy reduce
cell viability in cancer cells by affecting a broad number of cellular processes
(Kops et al.
2004
; Thompson and Compton
2008
; Williams et al.
2008
). Thus,
under normal circumstances, high levels of genetic instability impair cell growth,
unless the mutations introduced provide a selective pressure for the accumulation
of further changes, allowing cells to survive the adverse effects of aneuploidy
(Holland and Cleveland
2009
).
Aneuploidy or CIN can arise from defects in chromosome segregation during
mitosis. Cells may gain or lose chromosomes as a result of defects in the mitotic
checkpoint or in sister chromatid cohesion, of microtubule misattachments and of
aberrant mitotic division (reviewed by Kops et al.
2005
). The major cell cycle
checkpoint ensuring the correct segregation of chromosomes between daughter
cells is the spindle assembly checkpoint (SAC), which prevents metaphase-ana-
phase transition until all kinetochores have established a correct bi-orientation on
the spindle (Musacchio and Salmon
2007
). In mammalian cells, the complete
inactivation of the mitotic spindle checkpoint results in cell death and early
embryonic lethality due to massive chromosome missegregation (Kalitsis et al.
2000
; Kops et al.
2004
). However, altered expression or mutations in genes coding
for components of the SAC have been observed in aneuploid human cancers
(Cahill et al.
1998
; Dai et al.
2004
; Li et al.
2003
). In these cells, the mitotic
checkpoint is impaired and anaphase can begin even in the presence of unattached
or misattached kinetochores, leading to chromosome missegregation and aneu-
ploidy (Hanks et al.
2004
; Sotillo et al.
2007
).
Chromosome missegregation events may also occur following the generation of
incorrect kinetochore-microtubule attachments. When one kinetochore interacts
with microtubules coming from both spindle poles (merotelic attachment), the
chromosome is attached and under tension, so that the SAC is not activated and cells
can exit mitosis without any significant delay (Cimini et al.
2004
; Khodjakov et al.
1997
). Merotelic attachments are usually corrected before anaphase onset, although
occasionally sister chromatids with merotelic attachment can missegregate, failing
to move in either direction and yielding a lagging chromosome (reviewed by Salmon
et al.
2005
). At the end of mitosis, the lagging chromatid will be pushed into either
one of the daughter cells, and upon nuclear envelope reassembly, will form a separate
micronucleus (Cimini et al.
2002
). A further source of CIN arises when cells enter
mitosis
with
more
than
two
centrosomes
(Holland
and
Cleveland
2009
).
