Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression

Funk, Laura C.; Zasadil, Lauren M.; Weaver, Beth A.

doi:10.1016/j.devcel.2016.10.023

Cited by 128 publications

(135 citation statements)

References 144 publications

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“…Because chromosome segregation errors can be observed during mitosis, much work has focussed on elucidating mitotic defects that contribute to chromosomal instability (CIN) in cancer. A brief summary of these defects is given below as this subject has been extensively covered elsewhere (Funk et al 2016, Naylor & van Deursen 2016, Sansregret & Swanton 2017. Proper control of the dynamics of microtubules is essential for the correct attachment of chromosomes to the mitotic spindle.…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

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Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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“…[16,32,72,95,96] These inconsistent findings may be explained by different rates and types of CIN in the various models. Indeed, it has been suggested that high rates of CIN inhibit tumor progression, while lower CIN rates allow for tumor evolution [5,93,94] (also see Figure 2b and c). Importantly, CIN does not only seem to affect cancer growth, but also the ability of cancer to adapt and spread as transient CIN induction can lead to tumor recurrence.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 96%

“…On the one hand CIN itself can lead to tumorigenesis in some models, [91,92] but on the other hand, CIN has been found to act as a tumor suppressor in other models. [75,93,94] Furthermore, yet other CIN models are suggesting that CIN only enhances tumorigenesis in a tumorprone background. [16,32,72,95,96] These inconsistent findings may be explained by different rates and types of CIN in the various models.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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“…However, most cancer cell lines show genomic instability, defined as either chromosomal instability (CIN) or microsatellite instability (MIN) [25]. CIN is characterized by aneuploidy due to chromosomal mis-segregation during mitosis [26,27]. U2OS cells Table 2 Cases of genome editing-mediated disease modeling in human cultured cells …”

Section: Cancer Cell Linesmentioning

confidence: 99%

Updated summary of genome editing technology in human cultured cells linked to human genetics studies

2017

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Current deep-sequencing technology provides a mass of nucleotide variations associated with human genetic disorders to accelerate the identification of causative mutations. To understand the etiology of genetic disorders, reverse genetics in human cultured cells is a useful approach for modeling a disease in vitro. However, gene targeting in human cultured cells is difficult because of their low activity of homologous recombination. Engineered endonucleases enable enhancement of the local activation of DNA repair pathways at the human genome target site to rewrite the desired sequence, thereby efficiently generating disease-modeling cultured cell clones. These edited cells can be used to explore the molecular functions of a causative gene product to uncover the etiological mechanisms. The correction of mutations in patient cells using genome editing technology could contribute to the development of unique gene therapies. This technology can also be applied to screening causative mutations. Rare genetic disorders and non-exonic mutation-caused diseases remain frontier in the field of human genetics as it is difficult to validate whether the extracted nucleotide variants are mutation or polymorphism. When isogenic human cultured cells with a candidate variant reproduce the pathogenic phenotypes, it is confirmed that the variant is a causative mutation.

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Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression

Cited by 128 publications

References 144 publications

Role of chromosomal instability in cancer progression

Role of chromosomal instability in cancer progression

CIN and Aneuploidy: Different Concepts, Different Consequences

Updated summary of genome editing technology in human cultured cells linked to human genetics studies

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