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Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.

Pihan GA - Front Oncol (2013)

Bottom Line: But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells.Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling.Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

No MeSH data available.


Related in: MedlinePlus

Possible outcomes of multipolar mitoses in cancer. A subset of cells with multipolar spindles carry mitosis to completion, resulting in highly aneuploidy cells, some with abnormal centrosome number (A). Others fail cytokinesis resulting in giant multinucleated polyploid cells, often with supernumerary centrosomes (B). Some cells exit mitosis in a process termed “mitotic slippage” and become polyploid cells with supernumerary centrosomes (F), or apoptose in the subsequent G1 phase (E). Yet others undergo mitotic catastrophe (death in mitosis) (C). Finally, most cells with multipolar mitosis, after significant delay, reconfigure their multipolar spindles into bipolar spindles resulting in (mostly) normal or abnormal (merothelic, synthelic chromosome) chromosome segregation (D). The thickness of the arrows in the figure intends to provide an estimate of the frequency of these events in cancer cells.
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Figure 5: Possible outcomes of multipolar mitoses in cancer. A subset of cells with multipolar spindles carry mitosis to completion, resulting in highly aneuploidy cells, some with abnormal centrosome number (A). Others fail cytokinesis resulting in giant multinucleated polyploid cells, often with supernumerary centrosomes (B). Some cells exit mitosis in a process termed “mitotic slippage” and become polyploid cells with supernumerary centrosomes (F), or apoptose in the subsequent G1 phase (E). Yet others undergo mitotic catastrophe (death in mitosis) (C). Finally, most cells with multipolar mitosis, after significant delay, reconfigure their multipolar spindles into bipolar spindles resulting in (mostly) normal or abnormal (merothelic, synthelic chromosome) chromosome segregation (D). The thickness of the arrows in the figure intends to provide an estimate of the frequency of these events in cancer cells.

Mentions: Regardless of the mechanism of origin, supernumerary centrosomes pose the same initial challenge to dividing cells: once two or more functionally mature centrosomes are present at the G2 phase of the cell cycle, the potential for multipolar spindles, and chromosome missegregation on the next mitosis is very real. However, the outcome of multipolar mitoses differs significantly depending on a number of additional factors (Figure 5). One key factor is the ploidy of the dividing cell, which influences the success rate of multipolar mitoses (see above). Additional factors include the ability of cancer cells with multipolar mitoses to circumvent the mitotic spindle assembly checkpoint (326); the competence of cell death execution pathways leading to mitotic (327) or post-mitotic cell death (328) of cells that cannot self-correct defects to satisfy the mitotic assembly checkpoint; the ability of the cell to exit mitosis without experiencing anaphase and cytokinesis – a process that has been termed “mitotic slippage”; and more importantly, the ability of the cell to reconfigure the multipolar spindle into a bipolar spindle before entering anaphase (328, 329) (Figure 5).


Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.

Pihan GA - Front Oncol (2013)

Possible outcomes of multipolar mitoses in cancer. A subset of cells with multipolar spindles carry mitosis to completion, resulting in highly aneuploidy cells, some with abnormal centrosome number (A). Others fail cytokinesis resulting in giant multinucleated polyploid cells, often with supernumerary centrosomes (B). Some cells exit mitosis in a process termed “mitotic slippage” and become polyploid cells with supernumerary centrosomes (F), or apoptose in the subsequent G1 phase (E). Yet others undergo mitotic catastrophe (death in mitosis) (C). Finally, most cells with multipolar mitosis, after significant delay, reconfigure their multipolar spindles into bipolar spindles resulting in (mostly) normal or abnormal (merothelic, synthelic chromosome) chromosome segregation (D). The thickness of the arrows in the figure intends to provide an estimate of the frequency of these events in cancer cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824400&req=5

Figure 5: Possible outcomes of multipolar mitoses in cancer. A subset of cells with multipolar spindles carry mitosis to completion, resulting in highly aneuploidy cells, some with abnormal centrosome number (A). Others fail cytokinesis resulting in giant multinucleated polyploid cells, often with supernumerary centrosomes (B). Some cells exit mitosis in a process termed “mitotic slippage” and become polyploid cells with supernumerary centrosomes (F), or apoptose in the subsequent G1 phase (E). Yet others undergo mitotic catastrophe (death in mitosis) (C). Finally, most cells with multipolar mitosis, after significant delay, reconfigure their multipolar spindles into bipolar spindles resulting in (mostly) normal or abnormal (merothelic, synthelic chromosome) chromosome segregation (D). The thickness of the arrows in the figure intends to provide an estimate of the frequency of these events in cancer cells.
Mentions: Regardless of the mechanism of origin, supernumerary centrosomes pose the same initial challenge to dividing cells: once two or more functionally mature centrosomes are present at the G2 phase of the cell cycle, the potential for multipolar spindles, and chromosome missegregation on the next mitosis is very real. However, the outcome of multipolar mitoses differs significantly depending on a number of additional factors (Figure 5). One key factor is the ploidy of the dividing cell, which influences the success rate of multipolar mitoses (see above). Additional factors include the ability of cancer cells with multipolar mitoses to circumvent the mitotic spindle assembly checkpoint (326); the competence of cell death execution pathways leading to mitotic (327) or post-mitotic cell death (328) of cells that cannot self-correct defects to satisfy the mitotic assembly checkpoint; the ability of the cell to exit mitosis without experiencing anaphase and cytokinesis – a process that has been termed “mitotic slippage”; and more importantly, the ability of the cell to reconfigure the multipolar spindle into a bipolar spindle before entering anaphase (328, 329) (Figure 5).

Bottom Line: But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells.Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling.Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.

ABSTRACT
The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

No MeSH data available.


Related in: MedlinePlus