The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

Abstract

An increase in centrosome number is commonly observed in cancer cells, but the role centrosome amplification plays along with how and when it occurs during cancer development is unclear. One mechanism for generating cancer cells with extra centrosomes is whole genome doubling (WGD), an event that occurs in over 30% of human cancers and is associated with poor survival. Newly formed tetraploid cells can acquire extra centrosomes during WGD, and a generally accepted model proposes that centrosome amplification in tetraploid cells promotes cancer progression by generating aneuploidy and chromosomal instability. Recent findings, however, indicate that newly formed tetraploid cells in vitro lose their extra centrosomes to prevent multipolar cell divisions. Rather than persistent centrosome amplification, this evidence raises the possibility that it may be advantageous for tetraploid cells to initially restore centrosome number homeostasis and for a fraction of the population to reacquire additional centrosomes in the later stages of cancer evolution. In this review, we explore the different evolutionary paths available to newly formed tetraploid cells, their effects on centrosome and chromosome number distribution in daughter cells, and their probabilities of long-term survival. We then discuss the mechanisms that may alter centrosome and chromosome numbers in tetraploid cells and their relevance to cancer progression following WGD.

Aurora B inhibition promotes a hyper-polyploid state and continued endomitotic cycles in RB and p53 defective cells

“…We have demonstrated using 1 day treatment with AZD2811 to produced tetraploid cells that these can form viable colonies and have long term proliferative potential as diploid and tetraploid colonies. This supports the detailed fate studies of enforced tetraploid cells demonstrating reduced long term proliferative potential but stable tetraploid progeny is a potential outcome [37,45], and the genomics data demonstrating that tetraploidy can be tolerated by tumour cells [9], and In contrast to tetraploid cells, cells that undergo >2 failed cytokinesis and accumulate >8n DNA content and a corresponding increase in centrosome number have lost colony forming ability and long term proliferative potential. Indeed, in many of these experiments, exposure to AURKBi for the initial 2-3 days was sufficient to drive continued endomitotic cycles of failed cytokinesis.…”

“…It also appears that once cells have failed cytokinesis twice, they will continue to undergo further endomitotic cycles with failed cytokinesis in the absence of AURKBi. The increased centrosomes numbers and their ability to form individual mitotic spindles at each mitosis, rather than cluster to form pseudo-bipolar spindles that have been shown to enable relatively normal mitosis although commonly leading to cell death in subsequent mitosis [36,43,45]. The loss requirement for continued AURKBi treatment after 2-3 days is likely to be due to an inability of the mitotic, multipolar (>8 poles), hyper-polyploid (>8n DNA) cells to satisfy the spindle assembly checkpoint and undergo mitotic slippage without cytokinesis.…”

Adaptation of human cell populations to different levels of centriole amplification involves a two-step response

“…Cells with too many centrioles might divide abnormally and/or undergo cell cycle arrest, leading to reduced proliferation or even cell death. Thus, centriole numbers appear to be maintained at an equilibrium by a balance of centriole overproduction and negative selection acting on cells with extra centrioles 26,33 . However, most studies are limited to investigating short-term effects and transient centriole number alterations.…”