Biology Reference
In-Depth Information
subsequent induction of CIN that leads to malignant transformation (Basto et al.
2008
).
Consistent with such a scenario is the same sequence of events in D. melanogaster
larval neuroblasts containing mutations in genes that directly control asymmetric cell
division (Caussinus and Gonzalez
2005
).
The reason why asymmetric division fails in cells with supernumerary centrosomes
remains unclear. One possibility is that the asymmetric features of mother versus
daughter centrosomes which for example determine MT nucleation potentials are
disturbed by clustering of multiple centrosomes. Alternatively, astral MT organization,
which is important for the interaction between cell cortex and spindle poles and
therefore inherently linked to asymmetric division might be corrupted by centrosome
clustering. Third, supernumerary centrosomes seem to prevent asymmetric localiza-
tion of polarity determinants like MUD (the D. melanogaster homolog of the human
spindle pole protein NUMA) (Caussinus and Gonzalez
2005
), what in turn might
induce spindle positioning defects and disturbed asymmetric division.
To separately assess the contribution of centrosome defects versus CIN in
tumorigenesis, Castellanos and coworkers studied the tumorigenic potential of
multiple D. melanogaster larval brain tissue mutants defective in various aspects of
centrosome biogenesis (Castellanos et al.
2008
). Mutations affecting proteins
required for centriole replication, pericentriolar matrix recruitment and centrosome
function resulted in frequent tumor formation despite only a small fraction of cells
having abnormal karyotypes. Consistently, mutations known to induce CIN,
including defects in DNA replication and SAC, chromatin condensation and cyto-
kinesis did not give rise to tumors. These results again suggest that in tissues where
self-renewing asymmetric divisions are frequent, centrosome-related disturbed stem
cell division rather than induction of CIN might initiate malignant transformation.
Do these thought-provoking results imply that centrosome aberrations do
indeed cause cancer, however not via CIN as initially thought, but rather by
perturbing stem cell division? Given the possible cell-type- and organism-specific
effects, and the presence of moderate CIN along with the perturbed stem cell
divisions, this conclusion seems premature. Furthermore, we urgently need
insights into centrosome function in mammalian cancer stem cells. Answering the
question of whether supernumerary centrosomes contribute to mammalian
tumorigenesis by disruption of asymmetric division of cancer stem cells, induction
of CIN, or both will be rewarding.
17.5 Inhibition of Centrosome Clustering as a Novel
Anti-Cancer Treatment Strategy
Supernumerary centrosomes almost exclusively occur in a wide variety of
neoplastic disorders but only rarely in non-transformed cells. Therefore, inhibition
of centrosomal clustering with consequential induction of multipolar spindles and
subsequent cell death would specifically target tumor cells with no effect on
normal cells with a regular centrosome content (Nigg
2002
; Brinkley
2001
).
