Biology Reference
In-Depth Information
Centrosomes play a fundamental role in the organisation of the mitotic spindle. In
the presence of supernumerary centrosomes, multipolar spindles may form and
contribute to aneuploidy, although how such aneuploidy arises is not yet fully
understood.
13.2 Centrosome Abnormalities and Tumorigenesis
In 1902, Theodor Boveri first described the detrimental effects on organism and
cell physiology of an abnormal chromosome number. Several years earlier, the
pathologist David Hansemann had observed the presence of aberrant chromosome
segregation during mitosis in cancer cells. These findings led Boveri to propose
that aneuploidy might promote tumorigenesis. In 1914, following his studies on
sea urchin embryos, Boveri observed that cells forced to undergo multipolar
mitosis produced progeny with an aberrant chromosome number. The prevalence
of chromosome aberrations in cancer cells led Boveri to suggest that they were the
result of multipolar mitoses in cells with supernumerary centrosomes (reviewed by
Boveri
2008
; Godinho et al.
2009
; Holland and Cleveland
2009
).
Since 1914, several studies have shown that supernumerary centrosomes are
common to almost all types of solid and haematological malignancies, including
breast, brain, lung, colon, ovary, liver, prostate, bone, gall bladder, head and neck
cancers as well as lymphoma and leukaemia (Gustafson et al.
2000
; Kramer et al.
2003
; Kuo et al.
2000
; Lingle et al.
1998
; Nitta et al.
2006
; Pihan et al.
1998
; Pihan
et al.
2001
; Sato et al.
1999
; Weber et al.
1998
). Furthermore, in cancer cells,
aberrations in centrosome number are often associated with structural irregularities
such as increased centrosome size and alterations in the expression and phosphor-
ylation status of PCM components (Lingle et al.
2002
). Aberrant centrosomes often
exhibit aberrant recruitment of gamma-TuRCs and defects in microtubule nucle-
ation, which, in turn, affect the cellular architecture (Lingle et al.
2002
; Lingle and
Salisbury
2001
). Furthermore, it has been shown that centrosome abnormalities
correlate with increased levels of multipolar mitosis and aneuploidy in cancer cells
(Ghadimi et al.
2000
; Gisselsson et al.
2004
). Several studies showed that in highly
invasive cancers and in situ carcinoma, centrosomal defects are often associated
with chromosomal aberrations, which occur at a later stage in tumor progression
(Gisselsson et al.
2004
; Lingle et al.
2002
; Pihan et al.
2001
). However, centrosome
defects were also identified in cancers at an early stage in animal models and were
shown to become more severe with tumour progression (D'Assoro et al.
2002a
;
Duensing et al.
2001
; Goepfert et al.
2002
; Shono et al.
2001
). Although extra
centrosomes failed to generate large-scale genome instability in Drosophila, likely
due to the low proliferative index of mature Drosophila cells, serial transplantation
in the abdomen of adult flies of larval brain cells carrying mutations in genes that
encode centrosomal regulators and showing centrosome amplification, generated
both benign and malignant hyperplasia, demonstrating that centrosome amplifica-
tion can initiate tumorigenesis in flies (Castellanos et al.
2008
). While these
