Limits...
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

Leo Hansemann’s drawings of abnormal mitoses in cancer tissue. Abnormal metaphases (13, 30, 32, 33, 35), anaphases (8, 29), and telophases (31) are exquisitely represented, with many of the drawings implying supernumerary centrosomes, which could not be directly visualized in these preparations. Apparent mitotic catastrophes are represented as well (28, 34) (reproduced with permission from Virchows Archive). Hansemann took care of placing cancer tissue samples in warm fixative immediately after surgical resection to avoid anoxia-induced changes and in the process beautifully preserved spindle microtubules.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824400&req=5

Figure 1: Leo Hansemann’s drawings of abnormal mitoses in cancer tissue. Abnormal metaphases (13, 30, 32, 33, 35), anaphases (8, 29), and telophases (31) are exquisitely represented, with many of the drawings implying supernumerary centrosomes, which could not be directly visualized in these preparations. Apparent mitotic catastrophes are represented as well (28, 34) (reproduced with permission from Virchows Archive). Hansemann took care of placing cancer tissue samples in warm fixative immediately after surgical resection to avoid anoxia-induced changes and in the process beautifully preserved spindle microtubules.

Mentions: An abnormal complement of chromosomes, i.e., aneuploidy, is arguably the first identified hallmark of cancer cells. Beginning in 1890 Leo Hansemann, in a series of beautifully illustrated observations (Figure 1), documented the frequent presence of asymmetric and multipolar mitoses in carcinoma tissue (4, 5). Though uncertain of the significance of his findings, Hansemann was aware that daughter cells resulting from asymmetric mitoses received abnormal amounts of “chromatin.” Perhaps in part prompted by these findings, Theodore Boveri, who was aware of Leo Hansemann’s work and publically acknowledged his findings, formulated his now famous theory of cancer development (6). Half a century later, Torbjörn Caspersson, who pioneered cytological microspectrofluorimetric analysis of nuclei acids (7), would resoundingly confirm Hansemann and Boveri’s predictions. Caspersson was the first to observe that cancer cells, unlike normal cells, which always contained a constant amount of DNA, almost always exhibited greater, but highly variable quantities of nuclear DNA (8). It can thus be stated that an abnormal chromosome complement, possibly resulting from abnormal centrosome function, was the first hallmark of cancer ever identified. Since these pioneering observations, the nearly universal occurrence of abnormal chromosomes in cancer, in a bewildering combination of numerical and structural abnormalities, has been widely documented. A number of data repositories, such as The Cancer Genome Anatomy Project (9, 10), which includes Mitelman’s cancer cytogenetic collection currently containing 62,601 cancer karyotypes (11), provide a plethora of data and an overview of the spectrum and extent of large scale genome changes in cancer.


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

Pihan GA - Front Oncol (2013)

Leo Hansemann’s drawings of abnormal mitoses in cancer tissue. Abnormal metaphases (13, 30, 32, 33, 35), anaphases (8, 29), and telophases (31) are exquisitely represented, with many of the drawings implying supernumerary centrosomes, which could not be directly visualized in these preparations. Apparent mitotic catastrophes are represented as well (28, 34) (reproduced with permission from Virchows Archive). Hansemann took care of placing cancer tissue samples in warm fixative immediately after surgical resection to avoid anoxia-induced changes and in the process beautifully preserved spindle microtubules.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Leo Hansemann’s drawings of abnormal mitoses in cancer tissue. Abnormal metaphases (13, 30, 32, 33, 35), anaphases (8, 29), and telophases (31) are exquisitely represented, with many of the drawings implying supernumerary centrosomes, which could not be directly visualized in these preparations. Apparent mitotic catastrophes are represented as well (28, 34) (reproduced with permission from Virchows Archive). Hansemann took care of placing cancer tissue samples in warm fixative immediately after surgical resection to avoid anoxia-induced changes and in the process beautifully preserved spindle microtubules.
Mentions: An abnormal complement of chromosomes, i.e., aneuploidy, is arguably the first identified hallmark of cancer cells. Beginning in 1890 Leo Hansemann, in a series of beautifully illustrated observations (Figure 1), documented the frequent presence of asymmetric and multipolar mitoses in carcinoma tissue (4, 5). Though uncertain of the significance of his findings, Hansemann was aware that daughter cells resulting from asymmetric mitoses received abnormal amounts of “chromatin.” Perhaps in part prompted by these findings, Theodore Boveri, who was aware of Leo Hansemann’s work and publically acknowledged his findings, formulated his now famous theory of cancer development (6). Half a century later, Torbjörn Caspersson, who pioneered cytological microspectrofluorimetric analysis of nuclei acids (7), would resoundingly confirm Hansemann and Boveri’s predictions. Caspersson was the first to observe that cancer cells, unlike normal cells, which always contained a constant amount of DNA, almost always exhibited greater, but highly variable quantities of nuclear DNA (8). It can thus be stated that an abnormal chromosome complement, possibly resulting from abnormal centrosome function, was the first hallmark of cancer ever identified. Since these pioneering observations, the nearly universal occurrence of abnormal chromosomes in cancer, in a bewildering combination of numerical and structural abnormalities, has been widely documented. A number of data repositories, such as The Cancer Genome Anatomy Project (9, 10), which includes Mitelman’s cancer cytogenetic collection currently containing 62,601 cancer karyotypes (11), provide a plethora of data and an overview of the spectrum and extent of large scale genome changes in cancer.

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