Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors

Silk, Alain D.; Zasadil, Lauren M.; Holland, Andrew J.; Vitre, Benjamin; Cleveland, Don W.; Weaver, Beth A.

doi:10.1073/pnas.1317042110

Cited by 220 publications

(228 citation statements)

References 51 publications

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“…A strong cooperation between hepatocytes and mesenchymal cells and between the different nonparenchymal cell types occurs during liver injury (Gressner & Bachem, 1994). Meanwhile, the aneuploidy cells which appear in the sub‐G0/G1 population in our cell sorting analysis inherently trigger cell death (Liu et al ., 2012; Silk et al ., 2013). The increasing number of aneuploidy hepatocytes suggests an enhanced death of hepatocytes and consequently liver dysfunction and termination of mouse lifespan.…”

Section: Discussionmentioning

confidence: 99%

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Fei

et al. 2016

Aging Cell

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SummaryAutophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule‐associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectin mRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S‐mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild‐type mice increases the levels of fibronectin and γ‐H2 AX, a marker of DNA double‐strand breakage. LC3‐induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild‐type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3‐induced overexpression of fibronectin imposes stresses on MAP1S‐deficient mice and dramatically reduces their lifespans. Therefore, MAP1S‐mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.

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Section: Discussionmentioning

confidence: 99%

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Fei

et al. 2016

Aging Cell

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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%

“…[5,17,18,23,70] These mis-segregation events will lead to karyotype heterogeneity and karyotype evolution in the cell population and might explain the low rate of aneuploidy and karyotype evolution in cell cultures in which no (additional) CIN is induced (see Figure 2a for an example of karyotype evolution with low CIN). However, whether this "low-grade background" CIN rate is representative for the in vivo situation still needs to be assessed.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

“…The consequences of CIN likely depend on the severity of the chromosomal abnormality, the cell's microenvironment, and the cell type in which CIN took place. [3][4][5] While CIN and aneuploidy are used interchangeably, it is important to understand the difference. Aneuploidy is a genetic state, whereas CIN is the cellular behavior that leads to aneuploidy, see Figure 1 and Table 1 for further clarification.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Such multipolar mitoses, which result from the presence of extra centrosomes, provoke asymmetric cell divisions in which chromosomes are close-to-randomly distributed among three or more daughter cells (12,17). Exceptionally, newly generated aneuploid cells are fitter than their tetraploid progenitors, thus progressively transforming into malignant cells (2)(3)(4)(5)18).…”

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confidence: 99%

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

Lissa

Senovilla

Rello-Varona

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc Min/+ mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

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Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors

Cited by 220 publications

References 51 publications

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

CIN and Aneuploidy: Different Concepts, Different Consequences

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

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