Chromosome missegregation compromises the proliferation capacity of diploid cells, indicating that elevated missegregation rates alone are insufficient to generate viable aneuploid cells. The generation of aneuploid cells with sustained CIN requires both elevated chromosome missegregation rates and additional phenotypic changes that permit propagation of nondiploid cells. [@thompson_examining_2008]
Definitions
- chromosome missegregation
- diploid
- aneuploidaneuploidy
- aneuploid
- chromosomal instability
- cell proliferation
- phenotypic changes
Synthesis
Multiple lines of evidence establish that chromosome missegregation by itself is insufficient to enable aneuploid cell propagation, as aneuploidy consistently imposes fundamental fitness costs including impaired cell proliferation, altered metabolic properties, and reduced immortalization capacity across diverse experimental systems. The mechanistic basis for this constraint appears to involve pleiotropic cellular stress arising from chromosomal imbalance, which must be overcome through additional genetic alterations such as Stat1 inactivation combined with Myc activation to suppress immune infiltration and enable tumor progression. While elevated merotely can experimentally induce chromosomal instability in otherwise stable near-diploid cells, demonstrating that missegregation mechanisms are sufficient to generate aneuploidy, the observation that even chromosomally unstable lymphomas converge on specific recurrent chromosome gains suggests that ongoing missegregation is counteracted by strong selection pressures favoring particular karyotypes. What remains contested is the dual role of aneuploidy itself, which paradoxically drives spontaneous tumor formation in aged animals while simultaneously suppressing chemically or genetically induced tumorigenesis, indicating that the relationship between chromosome missegregation, resulting aneuploidy, and cellular fitness depends critically on cellular context and cooperating genetic changes.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Mps1 truncation-induced CIN generates convergent recurrent chromosome gains
- Merotely causes chromosome missegregation in unstable cells
- Aneuploidy alters cellular metabolic properties
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploidy impairs cell proliferation in trisomic lines
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Extra centrosomes correlate with chromosomal instability in tumors
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- CIN exists independently of classic mitotic defects in most cells
- Single-cell sequencing reveals karyotype heterogeneity in lymphomas
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- Aneuploidy decreases both organismal and cellular fitness
- Elevated merotely generates CIN in stable near-diploid cells
- Gene expression levels can computationally infer large-scale copy number variations in chromosomally unstable cells
- CENP-E reduction generates aneuploidy and chromosomal instability
- Aneuploidy affects cellular immortalization capacity