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Cancer karyotypes: survival of the fittest.

Nicholson JM, Cimini D - Front Oncol (2013)

Bottom Line: CIN can be caused by various mechanisms and results in extensive karyotypic heterogeneity within a cancer cell population.In this review we discuss the mechanisms of CIN, with particular emphasis on the role of aneuploidy on CIN.Further, we discuss the potential functional role of karyotypic patterns in cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech , Blacksburg, VA , USA.

ABSTRACT
Cancer cells are typically characterized by complex karyotypes including both structural and numerical changes, with aneuploidy being a ubiquitous feature. It is becoming increasingly evident that aneuploidy per se can cause chromosome mis-segregation, which explains the higher rates of chromosome gain/loss observed in aneuploid cancer cells compared to normal diploid cells, a phenotype termed chromosomal instability (CIN). CIN can be caused by various mechanisms and results in extensive karyotypic heterogeneity within a cancer cell population. However, despite such karyotypic heterogeneity, cancer cells also display predominant karyotypic patterns. In this review we discuss the mechanisms of CIN, with particular emphasis on the role of aneuploidy on CIN. Further, we discuss the potential functional role of karyotypic patterns in cancer.

No MeSH data available.


Related in: MedlinePlus

The degree of aneuploidy directly correlates with CIN, as measured by analysis of anaphase lagging chromosomes. One way to measure CIN is by determining the rates of anaphase lagging chromosomes in dividing cells. In a normal anaphase, chromosomes are equally segregated to the two poles of the mitotic spindle, as illustrated by the diagram in (A). Some dividing cells display anaphase lagging chromosomes (B), single chromosomes that lag behind at the cell equator as all the other chromosomes move to the spindle poles. Anaphase lagging chromosomes are caused by merotelic kinetochore attachment (Cimini et al., 2001), a kinetochore mis-attachment in which a single kinetochore is bound to microtubules from two spindle poles instead of just one. (C) XY plot showing the relation between anaphase lagging chromosomes and modal chromosome number in various cell lines. The graph also shows linear fits and regression values (R2). The three colors refer to data sets from different labs: red is for data from the Cimini Lab [(Silkworth et al., 2009) and (Silkworth, Nardi, and Cimini, unpublished)]; blue is for data from the Pellman lab (Ganem et al., 2009); green is for data from the Compton lab (Thompson and Compton, 2008). Karyotype information for cell lines from the Cimini Lab and the Pellman Lab was obtained from The American Type Cell Culture website (ATCC). Karyotype information for cell lines from the Compton Lab is that reported in (Thompson and Compton, 2008). Although there is a general trend in which higher chromosome modal number correlates with higher rates of anaphase lagging chromosomes, there is a certain degree of variability between different labs. Correlation analysis showed significant correlation between aneuploidy and CIN for the cell lines in blue (Pearson R = 0.85, P < 0.05) and those in red (Pearson R = 0.80, P < 0.05), but no significant correlation for the data shown in green (R = 0.71, P > 0.05).
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Figure 1: The degree of aneuploidy directly correlates with CIN, as measured by analysis of anaphase lagging chromosomes. One way to measure CIN is by determining the rates of anaphase lagging chromosomes in dividing cells. In a normal anaphase, chromosomes are equally segregated to the two poles of the mitotic spindle, as illustrated by the diagram in (A). Some dividing cells display anaphase lagging chromosomes (B), single chromosomes that lag behind at the cell equator as all the other chromosomes move to the spindle poles. Anaphase lagging chromosomes are caused by merotelic kinetochore attachment (Cimini et al., 2001), a kinetochore mis-attachment in which a single kinetochore is bound to microtubules from two spindle poles instead of just one. (C) XY plot showing the relation between anaphase lagging chromosomes and modal chromosome number in various cell lines. The graph also shows linear fits and regression values (R2). The three colors refer to data sets from different labs: red is for data from the Cimini Lab [(Silkworth et al., 2009) and (Silkworth, Nardi, and Cimini, unpublished)]; blue is for data from the Pellman lab (Ganem et al., 2009); green is for data from the Compton lab (Thompson and Compton, 2008). Karyotype information for cell lines from the Cimini Lab and the Pellman Lab was obtained from The American Type Cell Culture website (ATCC). Karyotype information for cell lines from the Compton Lab is that reported in (Thompson and Compton, 2008). Although there is a general trend in which higher chromosome modal number correlates with higher rates of anaphase lagging chromosomes, there is a certain degree of variability between different labs. Correlation analysis showed significant correlation between aneuploidy and CIN for the cell lines in blue (Pearson R = 0.85, P < 0.05) and those in red (Pearson R = 0.80, P < 0.05), but no significant correlation for the data shown in green (R = 0.71, P > 0.05).

Mentions: Most cancer cells are aneuploid and display a CIN phenotype. CIN can be caused by numerous mechanisms [reviewed in (Nicholson and Cimini, 2011)], including transient spindle geometry defects (Ganem et al., 2009; Silkworth et al., 2009; Silkworth and Cimini, 2012), impaired microtubule dynamics (Bakhoum et al., 2009a,b), and, rarely, a dysfunctional mitotic checkpoint (Cahill et al., 1998; Sato et al., 2000; Haruki et al., 2001), although the mitotic checkpoint is functional in most cancer cells (Tighe et al., 2001). Additionally, abnormal centrosome replication (Lingle et al., 2005) and DNA replication stress (Burrell et al., 2013; Janssen and Medema, 2013) have been proposed as mechanisms of CIN. Abnormal centrosome replication is likely to induce CIN by causing transient spindle geometry defects (Silkworth and Cimini, 2012). However, in the study by Burrell et al. replication stress did not seem related to whole-chromosome mis-segregation. Another mechanism emerging as a cause of CIN in cancer cells is aneuploidy itself (Duesberg et al., 1998; Thompson and Compton, 2010; Sheltzer et al., 2011; Nicholson et al., 2012; Zhu et al., 2012), although there has been disagreement on whether this is really the case, with a number of reports concluding that CIN is an aneuploidy-independent trait (Storchova and Kuffer, 2008; Zasadil et al., 2013). We believe that such disagreements primarily arise from two main issues: (i) there is confusion on how CIN is defined; (ii) different studies measure CIN in different ways. CIN has been loosely defined as an elevated rate of chromosome mis-segregation (Lengauer et al., 1997), yet how elevated and compared to what is often unclear (Geigl et al., 2008). Geigl et al. (2008) suggest that CIN can be defined as a significant increase in the rate of chromosome mis-segregation compared to an appropriate control cell population. Further, appropriate statistical tests must be employed (Geigl et al., 2008). Given this definition, many reports identifying stable aneuploidies can be reinterpreted. Studies that use data available in the Mitelman database of cancer karyotypes (Storchova and Kuffer, 2008; Mitelman et al., 2011; Zasadil et al., 2013) often rely on karyotypic analysis of small numbers (5–20) of cells per cancer, thus masking small rates of CIN that may be present (Adeyinka et al., 1998; Bridge et al., 2004). Other studies lack appropriate statistical analysis (Lengauer et al., 1997). Finally, stable is often used in relative terms. For instance, Roschke et al. (2002) identify stable aneuploid cancer cells in the presence of high rates of chromosome mis-segregation. These cells are considered stable because modal chromosome numbers do not deviate over time, despite deviations per chromosome of up to 20% at a given time (Roschke et al., 2002). The discrepancy between studies concluding that aneuploidy can cause CIN and those concluding that it does not may also stem from the method by which CIN is evaluated/measured in different studies. Many studies measure CIN by one of two methods: (i) performing karyotypic analysis (sometimes simply by chromosome count) at some point in time and measuring what fraction of the cell population possesses a chromosome number that deviates from the mode; (ii) performing FISH staining on interphase nuclei with chromosome-specific probes for two to three chromosomes and again evaluating what fraction of the cell population possesses a number of copies for those chromosomes that deviates from the mode. Neither of these methods really measures chromosome mis-segregation directly and both of them are very likely to underestimate the rates of chromosome mis-segregation occurring at each round of cell division. Because the gain or loss of a single chromosome represents a dramatic genetic change, whether a mis-segregation event can become evident as CIN using one of the methods described above will depend on a number of selective factors, including the specific chromosome that is lost or gained, the specific cell type studied, and the context (e.g., current karyotype, presence/absence of certain environmental conditions, etc.) in which the loss/gain occurs. In other words, cells that mis-segregate chromosomes may or may not survive, and therefore analysis of the karyotype in metaphase spreads or chromosome number in interphase nuclei may reveal a stable karyotype even in the presence of CIN. A more accurate way to measure CIN is by analyzing chromosome segregation in mitotic cells. Many labs have used this approach in recent years and found that CIN cells display higher rates of anaphase lagging chromosomes (chromosomes that lag behind at the cell equator while all other chromosomes segregate to the spindle poles, Figures 1A,B) compared to non-CIN cells (Thompson and Compton, 2008; Bakhoum et al., 2009a; Ganem et al., 2009; Silkworth et al., 2009). Anaphase lagging chromosomes, even when segregated to the correct daughter cell, still represent a mis-segregation event as they typically form micronuclei in the daughter cell (Cimini et al., 2002). Micronuclei have been shown to lead to both numerical and structural defects, including more anaphase lagging chromosomes (Crasta et al., 2012; He et al., 2012). Whereas the analysis of anaphase lagging chromosomes may be a better way to measure CIN, it may still be insufficient to determine the real rates of chromosome mis-segregation, as cases in which two sister chromatids segregate to the same spindle pole would go undetected. A good alternative approach to measure CIN would require the combination of more than one of the methods outlined above, such as, for instance, anaphase lagging chromosomes and interphase FISH or anaphase lagging chromosomes and karyotypic analysis. Alternatively, the analysis of anaphase lagging chromosomes (for all chromosomes) could be combined with analysis of chromosome segregation by FISH with chromosome-specific probes on anaphase cells and/or on binucleate cells in a cytokinesis-block assay (Cimini et al., 1999) and/or in the interphase ensuing cell division (Thompson and Compton, 2008).


Cancer karyotypes: survival of the fittest.

Nicholson JM, Cimini D - Front Oncol (2013)

The degree of aneuploidy directly correlates with CIN, as measured by analysis of anaphase lagging chromosomes. One way to measure CIN is by determining the rates of anaphase lagging chromosomes in dividing cells. In a normal anaphase, chromosomes are equally segregated to the two poles of the mitotic spindle, as illustrated by the diagram in (A). Some dividing cells display anaphase lagging chromosomes (B), single chromosomes that lag behind at the cell equator as all the other chromosomes move to the spindle poles. Anaphase lagging chromosomes are caused by merotelic kinetochore attachment (Cimini et al., 2001), a kinetochore mis-attachment in which a single kinetochore is bound to microtubules from two spindle poles instead of just one. (C) XY plot showing the relation between anaphase lagging chromosomes and modal chromosome number in various cell lines. The graph also shows linear fits and regression values (R2). The three colors refer to data sets from different labs: red is for data from the Cimini Lab [(Silkworth et al., 2009) and (Silkworth, Nardi, and Cimini, unpublished)]; blue is for data from the Pellman lab (Ganem et al., 2009); green is for data from the Compton lab (Thompson and Compton, 2008). Karyotype information for cell lines from the Cimini Lab and the Pellman Lab was obtained from The American Type Cell Culture website (ATCC). Karyotype information for cell lines from the Compton Lab is that reported in (Thompson and Compton, 2008). Although there is a general trend in which higher chromosome modal number correlates with higher rates of anaphase lagging chromosomes, there is a certain degree of variability between different labs. Correlation analysis showed significant correlation between aneuploidy and CIN for the cell lines in blue (Pearson R = 0.85, P < 0.05) and those in red (Pearson R = 0.80, P < 0.05), but no significant correlation for the data shown in green (R = 0.71, P > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675379&req=5

Figure 1: The degree of aneuploidy directly correlates with CIN, as measured by analysis of anaphase lagging chromosomes. One way to measure CIN is by determining the rates of anaphase lagging chromosomes in dividing cells. In a normal anaphase, chromosomes are equally segregated to the two poles of the mitotic spindle, as illustrated by the diagram in (A). Some dividing cells display anaphase lagging chromosomes (B), single chromosomes that lag behind at the cell equator as all the other chromosomes move to the spindle poles. Anaphase lagging chromosomes are caused by merotelic kinetochore attachment (Cimini et al., 2001), a kinetochore mis-attachment in which a single kinetochore is bound to microtubules from two spindle poles instead of just one. (C) XY plot showing the relation between anaphase lagging chromosomes and modal chromosome number in various cell lines. The graph also shows linear fits and regression values (R2). The three colors refer to data sets from different labs: red is for data from the Cimini Lab [(Silkworth et al., 2009) and (Silkworth, Nardi, and Cimini, unpublished)]; blue is for data from the Pellman lab (Ganem et al., 2009); green is for data from the Compton lab (Thompson and Compton, 2008). Karyotype information for cell lines from the Cimini Lab and the Pellman Lab was obtained from The American Type Cell Culture website (ATCC). Karyotype information for cell lines from the Compton Lab is that reported in (Thompson and Compton, 2008). Although there is a general trend in which higher chromosome modal number correlates with higher rates of anaphase lagging chromosomes, there is a certain degree of variability between different labs. Correlation analysis showed significant correlation between aneuploidy and CIN for the cell lines in blue (Pearson R = 0.85, P < 0.05) and those in red (Pearson R = 0.80, P < 0.05), but no significant correlation for the data shown in green (R = 0.71, P > 0.05).
Mentions: Most cancer cells are aneuploid and display a CIN phenotype. CIN can be caused by numerous mechanisms [reviewed in (Nicholson and Cimini, 2011)], including transient spindle geometry defects (Ganem et al., 2009; Silkworth et al., 2009; Silkworth and Cimini, 2012), impaired microtubule dynamics (Bakhoum et al., 2009a,b), and, rarely, a dysfunctional mitotic checkpoint (Cahill et al., 1998; Sato et al., 2000; Haruki et al., 2001), although the mitotic checkpoint is functional in most cancer cells (Tighe et al., 2001). Additionally, abnormal centrosome replication (Lingle et al., 2005) and DNA replication stress (Burrell et al., 2013; Janssen and Medema, 2013) have been proposed as mechanisms of CIN. Abnormal centrosome replication is likely to induce CIN by causing transient spindle geometry defects (Silkworth and Cimini, 2012). However, in the study by Burrell et al. replication stress did not seem related to whole-chromosome mis-segregation. Another mechanism emerging as a cause of CIN in cancer cells is aneuploidy itself (Duesberg et al., 1998; Thompson and Compton, 2010; Sheltzer et al., 2011; Nicholson et al., 2012; Zhu et al., 2012), although there has been disagreement on whether this is really the case, with a number of reports concluding that CIN is an aneuploidy-independent trait (Storchova and Kuffer, 2008; Zasadil et al., 2013). We believe that such disagreements primarily arise from two main issues: (i) there is confusion on how CIN is defined; (ii) different studies measure CIN in different ways. CIN has been loosely defined as an elevated rate of chromosome mis-segregation (Lengauer et al., 1997), yet how elevated and compared to what is often unclear (Geigl et al., 2008). Geigl et al. (2008) suggest that CIN can be defined as a significant increase in the rate of chromosome mis-segregation compared to an appropriate control cell population. Further, appropriate statistical tests must be employed (Geigl et al., 2008). Given this definition, many reports identifying stable aneuploidies can be reinterpreted. Studies that use data available in the Mitelman database of cancer karyotypes (Storchova and Kuffer, 2008; Mitelman et al., 2011; Zasadil et al., 2013) often rely on karyotypic analysis of small numbers (5–20) of cells per cancer, thus masking small rates of CIN that may be present (Adeyinka et al., 1998; Bridge et al., 2004). Other studies lack appropriate statistical analysis (Lengauer et al., 1997). Finally, stable is often used in relative terms. For instance, Roschke et al. (2002) identify stable aneuploid cancer cells in the presence of high rates of chromosome mis-segregation. These cells are considered stable because modal chromosome numbers do not deviate over time, despite deviations per chromosome of up to 20% at a given time (Roschke et al., 2002). The discrepancy between studies concluding that aneuploidy can cause CIN and those concluding that it does not may also stem from the method by which CIN is evaluated/measured in different studies. Many studies measure CIN by one of two methods: (i) performing karyotypic analysis (sometimes simply by chromosome count) at some point in time and measuring what fraction of the cell population possesses a chromosome number that deviates from the mode; (ii) performing FISH staining on interphase nuclei with chromosome-specific probes for two to three chromosomes and again evaluating what fraction of the cell population possesses a number of copies for those chromosomes that deviates from the mode. Neither of these methods really measures chromosome mis-segregation directly and both of them are very likely to underestimate the rates of chromosome mis-segregation occurring at each round of cell division. Because the gain or loss of a single chromosome represents a dramatic genetic change, whether a mis-segregation event can become evident as CIN using one of the methods described above will depend on a number of selective factors, including the specific chromosome that is lost or gained, the specific cell type studied, and the context (e.g., current karyotype, presence/absence of certain environmental conditions, etc.) in which the loss/gain occurs. In other words, cells that mis-segregate chromosomes may or may not survive, and therefore analysis of the karyotype in metaphase spreads or chromosome number in interphase nuclei may reveal a stable karyotype even in the presence of CIN. A more accurate way to measure CIN is by analyzing chromosome segregation in mitotic cells. Many labs have used this approach in recent years and found that CIN cells display higher rates of anaphase lagging chromosomes (chromosomes that lag behind at the cell equator while all other chromosomes segregate to the spindle poles, Figures 1A,B) compared to non-CIN cells (Thompson and Compton, 2008; Bakhoum et al., 2009a; Ganem et al., 2009; Silkworth et al., 2009). Anaphase lagging chromosomes, even when segregated to the correct daughter cell, still represent a mis-segregation event as they typically form micronuclei in the daughter cell (Cimini et al., 2002). Micronuclei have been shown to lead to both numerical and structural defects, including more anaphase lagging chromosomes (Crasta et al., 2012; He et al., 2012). Whereas the analysis of anaphase lagging chromosomes may be a better way to measure CIN, it may still be insufficient to determine the real rates of chromosome mis-segregation, as cases in which two sister chromatids segregate to the same spindle pole would go undetected. A good alternative approach to measure CIN would require the combination of more than one of the methods outlined above, such as, for instance, anaphase lagging chromosomes and interphase FISH or anaphase lagging chromosomes and karyotypic analysis. Alternatively, the analysis of anaphase lagging chromosomes (for all chromosomes) could be combined with analysis of chromosome segregation by FISH with chromosome-specific probes on anaphase cells and/or on binucleate cells in a cytokinesis-block assay (Cimini et al., 1999) and/or in the interphase ensuing cell division (Thompson and Compton, 2008).

Bottom Line: CIN can be caused by various mechanisms and results in extensive karyotypic heterogeneity within a cancer cell population.In this review we discuss the mechanisms of CIN, with particular emphasis on the role of aneuploidy on CIN.Further, we discuss the potential functional role of karyotypic patterns in cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech , Blacksburg, VA , USA.

ABSTRACT
Cancer cells are typically characterized by complex karyotypes including both structural and numerical changes, with aneuploidy being a ubiquitous feature. It is becoming increasingly evident that aneuploidy per se can cause chromosome mis-segregation, which explains the higher rates of chromosome gain/loss observed in aneuploid cancer cells compared to normal diploid cells, a phenotype termed chromosomal instability (CIN). CIN can be caused by various mechanisms and results in extensive karyotypic heterogeneity within a cancer cell population. However, despite such karyotypic heterogeneity, cancer cells also display predominant karyotypic patterns. In this review we discuss the mechanisms of CIN, with particular emphasis on the role of aneuploidy on CIN. Further, we discuss the potential functional role of karyotypic patterns in cancer.

No MeSH data available.


Related in: MedlinePlus