The antagonistic relationship between apoptosis and polyploidy in development and cancer

Abstract

One of the important functions of regulated cell death is to prevent cells from inappropriately acquiring extra copies of their genome, a state known as polyploidy. Apoptosis is the primary cell death mechanism that prevents polyploidy, and defects in this apoptotic response can result in polyploid cells whose subsequent error-prone chromosome segregation are a major contributor to genome instability and cancer progression. Conversely, some cells actively repress apoptosis to become polyploid as part of normal development or regeneration. Thus, although apoptosis prevents polyploidy, the polyploid state can actively repress apoptosis. In this review, we discuss progress in understanding the antagonistic relationship between apoptosis and polyploidy in development and cancer. Despite recent advances, a key conclusion is that much remains unknown about the mechanisms that link apoptosis to polyploid cell cycles. We suggest that drawing parallels between the regulation of apoptosis in development and cancer could help to fill this knowledge gap and lead to more effective therapies.

Keywords: Aneuploidy; Apoptosis; Endoreplication; Polyploidy; Regulated cell death; Tetraploid.

Figure 1.. Endoreplication cell cycles.

During the canonical mitotic cell cycle (left) diploid cells grow and divide (2C/4C). During endoreplication cycles (right) cells do not divide but increase in size and DNA content (4C-1000’sC). Endocycles skip mitosis and cytokinesis, whereas endomitotic cycles complete different extents of mitosis, and also skip cytokinesis. An endomitosis that completes nuclear division (karyokinesis) results in a binucleate, polyploid daughter cell.

Figure 2.. Developmental and induced endoreplication cycles.

Mitotically dividing diploid cells can switch to endoreplication in response to developmental signals. Cells can also switch to an unscheduled endoreplication program in response to conditional signals, including wound healing, aging, various stresses, or the experimental inhibition of mitosis. These developmental endoreplicating cells (devECs) and induced endoreplicating cells (iECs) both repress the apoptotic response to genotoxic stress through multiple mechanisms.

Figure 3.. Polyploid cancer cells bypass apoptosis and cell cycle arrest.

Various stresses induce a mitotic failure and a return to G1 with a 4C DNA content (tetraploid). Multiple pathways sense this mitotic failure and trigger apoptosis or cell cycle arrest. Cells with defects in these death and arrest pathways, or that upregulate activities that promote G1/S progression, can continue to cycle (see text for details). This bypass can result in proliferating tetraploid cells or endoreplicating polyploid giant cancer cells (PGCCs), the latter of which go through multiple endoreplication cycles. Most PGCCs reach a terminal ploidy and then senesce, but some can leave senescence and resume divisions. Dividing PGCCs and tetraploid cells have high levels of chromosomal instability (CIN), which leads to genetically diverse pools of aneuploid daughter cells that can acquire drug resistance and promote tumor progression.