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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

Pathways to supernumerary centrosomes in cancer. Canonical template-dependent centrosome replication pathway (A). Normal centrosome duplication proceeds sequentially in the following steps: centriole disengagement (1), linker fiber development (2), procentriole nucleation (3), centriole elongation (4), linker dissolution (5), centrosome maturation (6) and separation, before (7) and after (8) NEB. There are at least three pathways to supernumerary centrosomes in cancer (B–D). Centrosome accumulation pathway due to polyploidization events (B). Events such as cytokinesis failure, mitotic slippage (mitotic failure before cytokinesis), etc., with or without normal DNA replication, result in accumulation of normally replicated centrosomes, which execute all stages of replication as in the canonical template-dependent pathway A. Centrosome over-replication pathway (C). Some cancer cells, particularly if arrested in S or G2 phases, such as during DNA replication stress induced by hypoxia, chemotherapy or radiation therapy, undergo multiple rounds of templated centriole duplication (3′), which subsequently elongate (4′) and mature (5′) leading to functional centrosomes capable of enacting multipolar mitoses (6′). De novo centriole formation pathway (D). Under similar conditions certain cancer cells, even when containing resident centrosome, build new centrioles de novo, via centriole satellites (2′′). Once synthesized such centrioles (3′′) can elongate (4′′), mature by acquiring normal mitotic PCM (5′′), and become competent at mitosis (6′′) usually enacting multipolar spindles. In subsequent cell divisions, de novo centrosomes are thought to replicate via the canonical template-dependent pathway.
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Figure 4: Pathways to supernumerary centrosomes in cancer. Canonical template-dependent centrosome replication pathway (A). Normal centrosome duplication proceeds sequentially in the following steps: centriole disengagement (1), linker fiber development (2), procentriole nucleation (3), centriole elongation (4), linker dissolution (5), centrosome maturation (6) and separation, before (7) and after (8) NEB. There are at least three pathways to supernumerary centrosomes in cancer (B–D). Centrosome accumulation pathway due to polyploidization events (B). Events such as cytokinesis failure, mitotic slippage (mitotic failure before cytokinesis), etc., with or without normal DNA replication, result in accumulation of normally replicated centrosomes, which execute all stages of replication as in the canonical template-dependent pathway A. Centrosome over-replication pathway (C). Some cancer cells, particularly if arrested in S or G2 phases, such as during DNA replication stress induced by hypoxia, chemotherapy or radiation therapy, undergo multiple rounds of templated centriole duplication (3′), which subsequently elongate (4′) and mature (5′) leading to functional centrosomes capable of enacting multipolar mitoses (6′). De novo centriole formation pathway (D). Under similar conditions certain cancer cells, even when containing resident centrosome, build new centrioles de novo, via centriole satellites (2′′). Once synthesized such centrioles (3′′) can elongate (4′′), mature by acquiring normal mitotic PCM (5′′), and become competent at mitosis (6′′) usually enacting multipolar spindles. In subsequent cell divisions, de novo centrosomes are thought to replicate via the canonical template-dependent pathway.

Mentions: The most evident and widely documented centrosome cancer phenotype is supernumerary centrosomes (250, 251) (Figure 4). In principle, supernumerary centrosomes may result from at least three separate mechanisms: template-mediated over-replication of pre-existing centrosomes within one cell cycle (hereby termed the over-replication pathway), a phenotype that has been variably referred to as centrosome amplification (254, 263, 284–286) or hyperamplification (252, 255, 287, 288), de novo formation during interphase (de novo pathway) (289, 290) (Figure 4) or from accumulation of normally (or abnormally) replicated centrosomes due to failed cell division after replication of centrosomes and chromosomes has occurred (accumulation pathway) (291, 292) (Figure 4) [reviewed in Ref. (293, 294)]. While in the latter the normal numerical relationship of one centrosome per diploid chromosome set in G1 phase is maintained, in the former two pathways it is halved or worse. This difference profoundly affects the chances of daughter cell survival in cells carrying multipolar mitoses to completion, since daughter cell viability is predicated on receiving at least a full haploid set of chromosomes. This in fact is one of the seminal experimental observations made by Boveri in dispermic see urchin eggs, which allowed him to infer that chromosomes are not interchangeable and therefore must carry different genetic determinants (249).


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

Pihan GA - Front Oncol (2013)

Pathways to supernumerary centrosomes in cancer. Canonical template-dependent centrosome replication pathway (A). Normal centrosome duplication proceeds sequentially in the following steps: centriole disengagement (1), linker fiber development (2), procentriole nucleation (3), centriole elongation (4), linker dissolution (5), centrosome maturation (6) and separation, before (7) and after (8) NEB. There are at least three pathways to supernumerary centrosomes in cancer (B–D). Centrosome accumulation pathway due to polyploidization events (B). Events such as cytokinesis failure, mitotic slippage (mitotic failure before cytokinesis), etc., with or without normal DNA replication, result in accumulation of normally replicated centrosomes, which execute all stages of replication as in the canonical template-dependent pathway A. Centrosome over-replication pathway (C). Some cancer cells, particularly if arrested in S or G2 phases, such as during DNA replication stress induced by hypoxia, chemotherapy or radiation therapy, undergo multiple rounds of templated centriole duplication (3′), which subsequently elongate (4′) and mature (5′) leading to functional centrosomes capable of enacting multipolar mitoses (6′). De novo centriole formation pathway (D). Under similar conditions certain cancer cells, even when containing resident centrosome, build new centrioles de novo, via centriole satellites (2′′). Once synthesized such centrioles (3′′) can elongate (4′′), mature by acquiring normal mitotic PCM (5′′), and become competent at mitosis (6′′) usually enacting multipolar spindles. In subsequent cell divisions, de novo centrosomes are thought to replicate via the canonical template-dependent pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 4: Pathways to supernumerary centrosomes in cancer. Canonical template-dependent centrosome replication pathway (A). Normal centrosome duplication proceeds sequentially in the following steps: centriole disengagement (1), linker fiber development (2), procentriole nucleation (3), centriole elongation (4), linker dissolution (5), centrosome maturation (6) and separation, before (7) and after (8) NEB. There are at least three pathways to supernumerary centrosomes in cancer (B–D). Centrosome accumulation pathway due to polyploidization events (B). Events such as cytokinesis failure, mitotic slippage (mitotic failure before cytokinesis), etc., with or without normal DNA replication, result in accumulation of normally replicated centrosomes, which execute all stages of replication as in the canonical template-dependent pathway A. Centrosome over-replication pathway (C). Some cancer cells, particularly if arrested in S or G2 phases, such as during DNA replication stress induced by hypoxia, chemotherapy or radiation therapy, undergo multiple rounds of templated centriole duplication (3′), which subsequently elongate (4′) and mature (5′) leading to functional centrosomes capable of enacting multipolar mitoses (6′). De novo centriole formation pathway (D). Under similar conditions certain cancer cells, even when containing resident centrosome, build new centrioles de novo, via centriole satellites (2′′). Once synthesized such centrioles (3′′) can elongate (4′′), mature by acquiring normal mitotic PCM (5′′), and become competent at mitosis (6′′) usually enacting multipolar spindles. In subsequent cell divisions, de novo centrosomes are thought to replicate via the canonical template-dependent pathway.
Mentions: The most evident and widely documented centrosome cancer phenotype is supernumerary centrosomes (250, 251) (Figure 4). In principle, supernumerary centrosomes may result from at least three separate mechanisms: template-mediated over-replication of pre-existing centrosomes within one cell cycle (hereby termed the over-replication pathway), a phenotype that has been variably referred to as centrosome amplification (254, 263, 284–286) or hyperamplification (252, 255, 287, 288), de novo formation during interphase (de novo pathway) (289, 290) (Figure 4) or from accumulation of normally (or abnormally) replicated centrosomes due to failed cell division after replication of centrosomes and chromosomes has occurred (accumulation pathway) (291, 292) (Figure 4) [reviewed in Ref. (293, 294)]. While in the latter the normal numerical relationship of one centrosome per diploid chromosome set in G1 phase is maintained, in the former two pathways it is halved or worse. This difference profoundly affects the chances of daughter cell survival in cells carrying multipolar mitoses to completion, since daughter cell viability is predicated on receiving at least a full haploid set of chromosomes. This in fact is one of the seminal experimental observations made by Boveri in dispermic see urchin eggs, which allowed him to infer that chromosomes are not interchangeable and therefore must carry different genetic determinants (249).

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