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Aneuploidy and chromosomal instability in cancer: a jackpot to chaos.

Giam M, Rancati G - Cell Div (2015)

Bottom Line: On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis.Furthermore, mouse models for CIN have led to conflicting results.Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Biology (IMB), Agency for Science, Technology and Research (ASTAR), Singapore, 138648 Singapore.

ABSTRACT
Genomic instability (GIN) is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution. Chromosomal instability (CIN) is a form of GIN that involves frequent cytogenetic changes leading to changes in chromosome copy number (aneuploidy). While both CIN and aneuploidy are common characteristics of cancer cells, their roles in tumor initiation and progression are unclear. On the one hand, CIN and aneuploidy are known to provide genetic variation to allow cells to adapt in changing environments such as nutrient fluctuations and hypoxia. Patients with constitutive aneuploidies are more susceptible to certain types of cancers, suggesting that changes in chromosome copy number could positively contribute to cancer evolution. On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis. Furthermore, mouse models for CIN have led to conflicting results. Taken together these findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated. Here we review what is known about this complex ménage à trois, discuss recent evidence suggesting that aneuploidy, CIN and GIN together promote a vicious cycle of genome chaos. Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Aneuploidy, CIN and GIN loop together to tumorigenesis. Aneuploidy results in direct changes in mRNA and protein expression levels of genes found on the aneuploid chromosome. Increasing or decreasing the dosage of oncogenes (OG) and tumor suppressor genes (TSG) can have direct effects on cellular transformation. Additionally, while CIN leads to aneuploidy via increased chromosome missegregation, aneuploidy can lead to CIN by changing the stoichiometry of protein complexes required for genome maintenance or by scaling defects brought about by the presence of extra DNA. At the same time, chromosome missegregation has the potential to increase DNA damage and GIN. CIN and GIN are considered mutator phenotypes that could potentially enhance the chance of accumulating oncogenic mutations, thus promoting tumorigenesis. Their ‘by-products’, aneuploidy and DNA damage generate genetic variation, allowing cells to have increased adaptive potential in the tumor microenvironment
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Fig1: Aneuploidy, CIN and GIN loop together to tumorigenesis. Aneuploidy results in direct changes in mRNA and protein expression levels of genes found on the aneuploid chromosome. Increasing or decreasing the dosage of oncogenes (OG) and tumor suppressor genes (TSG) can have direct effects on cellular transformation. Additionally, while CIN leads to aneuploidy via increased chromosome missegregation, aneuploidy can lead to CIN by changing the stoichiometry of protein complexes required for genome maintenance or by scaling defects brought about by the presence of extra DNA. At the same time, chromosome missegregation has the potential to increase DNA damage and GIN. CIN and GIN are considered mutator phenotypes that could potentially enhance the chance of accumulating oncogenic mutations, thus promoting tumorigenesis. Their ‘by-products’, aneuploidy and DNA damage generate genetic variation, allowing cells to have increased adaptive potential in the tumor microenvironment

Mentions: Chromosomal instability (CIN) refers to an increased rate of chromosome missegregation due to errors in mitosis [24, 25]. One of the main products of CIN is aneuploidy, a condition associated with the gain or loss of whole chromosomes or parts thereof leading to genomic imbalances (Fig. 1). There are many roads leading to CIN: multipolar spindles, improper chromosome condensation or cohesion, inefficient chromosome congression, defects in mitotic spindle assembly/dynamics, defective mitotic checkpoint and telomere attrition, replication stress, and improper kinetochore-microtubules attachments [25–27]. To add even more complexity, recent studies proposed that aneuploidy itself could lead to CIN (Fig. 1 and discussed below), suggesting the presence of a positive feedback loop resulting in increasing levels of aneuploidy.Fig. 1


Aneuploidy and chromosomal instability in cancer: a jackpot to chaos.

Giam M, Rancati G - Cell Div (2015)

Aneuploidy, CIN and GIN loop together to tumorigenesis. Aneuploidy results in direct changes in mRNA and protein expression levels of genes found on the aneuploid chromosome. Increasing or decreasing the dosage of oncogenes (OG) and tumor suppressor genes (TSG) can have direct effects on cellular transformation. Additionally, while CIN leads to aneuploidy via increased chromosome missegregation, aneuploidy can lead to CIN by changing the stoichiometry of protein complexes required for genome maintenance or by scaling defects brought about by the presence of extra DNA. At the same time, chromosome missegregation has the potential to increase DNA damage and GIN. CIN and GIN are considered mutator phenotypes that could potentially enhance the chance of accumulating oncogenic mutations, thus promoting tumorigenesis. Their ‘by-products’, aneuploidy and DNA damage generate genetic variation, allowing cells to have increased adaptive potential in the tumor microenvironment
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4443636&req=5

Fig1: Aneuploidy, CIN and GIN loop together to tumorigenesis. Aneuploidy results in direct changes in mRNA and protein expression levels of genes found on the aneuploid chromosome. Increasing or decreasing the dosage of oncogenes (OG) and tumor suppressor genes (TSG) can have direct effects on cellular transformation. Additionally, while CIN leads to aneuploidy via increased chromosome missegregation, aneuploidy can lead to CIN by changing the stoichiometry of protein complexes required for genome maintenance or by scaling defects brought about by the presence of extra DNA. At the same time, chromosome missegregation has the potential to increase DNA damage and GIN. CIN and GIN are considered mutator phenotypes that could potentially enhance the chance of accumulating oncogenic mutations, thus promoting tumorigenesis. Their ‘by-products’, aneuploidy and DNA damage generate genetic variation, allowing cells to have increased adaptive potential in the tumor microenvironment
Mentions: Chromosomal instability (CIN) refers to an increased rate of chromosome missegregation due to errors in mitosis [24, 25]. One of the main products of CIN is aneuploidy, a condition associated with the gain or loss of whole chromosomes or parts thereof leading to genomic imbalances (Fig. 1). There are many roads leading to CIN: multipolar spindles, improper chromosome condensation or cohesion, inefficient chromosome congression, defects in mitotic spindle assembly/dynamics, defective mitotic checkpoint and telomere attrition, replication stress, and improper kinetochore-microtubules attachments [25–27]. To add even more complexity, recent studies proposed that aneuploidy itself could lead to CIN (Fig. 1 and discussed below), suggesting the presence of a positive feedback loop resulting in increasing levels of aneuploidy.Fig. 1

Bottom Line: On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis.Furthermore, mouse models for CIN have led to conflicting results.Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Biology (IMB), Agency for Science, Technology and Research (ASTAR), Singapore, 138648 Singapore.

ABSTRACT
Genomic instability (GIN) is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution. Chromosomal instability (CIN) is a form of GIN that involves frequent cytogenetic changes leading to changes in chromosome copy number (aneuploidy). While both CIN and aneuploidy are common characteristics of cancer cells, their roles in tumor initiation and progression are unclear. On the one hand, CIN and aneuploidy are known to provide genetic variation to allow cells to adapt in changing environments such as nutrient fluctuations and hypoxia. Patients with constitutive aneuploidies are more susceptible to certain types of cancers, suggesting that changes in chromosome copy number could positively contribute to cancer evolution. On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis. Furthermore, mouse models for CIN have led to conflicting results. Taken together these findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated. Here we review what is known about this complex ménage à trois, discuss recent evidence suggesting that aneuploidy, CIN and GIN together promote a vicious cycle of genome chaos. Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.

No MeSH data available.


Related in: MedlinePlus