Cellular stress has been implicated in many diseases, including cancer. During cancer progression, cellular stress promotes adaptive genome alterations, which increase the probability of somatic evolution.1
Multiple types of stress have been documented occurring through various molecular mechanisms, and some are linked to genome instability and apoptosis.2, 3
However, cell death occurs in a number of forms, and apoptosis does not adequately represent the amount of cell death that happens in tumors in response to chemotherapy or radiation.4
Apoptosis tends to occur in response to relatively high levels of drug treatment, often higher than clinical levels,5
and the exact functions of apoptotic proteins can be contextually dependent. For example, in some cases activation of apoptotic proteins may drive proliferation. Furthermore, tumor cells often overexpress antiapoptotic proteins or lack intact cell-cycle checkpoints.6
Loss of checkpoint function allows the cells to progress to mitosis despite the presence of damaged DNA, often resulting in mitotic cell death (MCD).
Although MCD accounts for the majority of tumor cell death during treatment, its mechanism(s) is largely unknown.5, 7, 8, 9
MCD appears as at least two major phenotypes: One is mitosis associated cell death, which occurs following abnormal segregation, where death takes place in G1
following abnormal division. This form of MCD is associated with classical apoptosis, as the caspase cascade is activated following entry of multinucleated cells into G1
, and is referred to as mitotic catastrophe (MC).9, 10
Another is chromosome fragmentation (C-Frag) that occurs directly during mitosis. It is readily identifiable in cytogenomic figures where degraded chromosomes are evident.9
To illustrate the basis of C-Frag, many diverse stresses leading to C-Frag are analyzed. A simple relationship between diverse system stresses and C-Frag is established. These stresses are shown to converge on the induction of centrosome amplification, a major component in the regulation of genome stability. Based on this relationship, the common mechanism of cell death is re-synthesized: (1) Cell death is a general response of the cellular system to stress, having a role in rebalancing the cellular system. C-Frag, a main phenotype of MCD, is achieved through an array of individual molecular mechanisms, including centrosome amplification. (2) The type of cell death that will dominate in a given sample is dependent on multiple factors, including the availability of both the targets in cells (checkpoint function, whether cells are actively dividing) and the specifics of drug treatment. (3) The types of cell death induced are heterogeneous, as shown by cytogenomic analysis. Such heterogeneity, in addition to genome-level heterogeneity,11, 12
explains why drug treatment can favor cancer evolution, as treatment induces stress leading to genome-mediated cancer evolution.1, 13
Recent reports have detailed processes where cassettes of fragmented chromosomes have been rejoined to form highly recombined chromosomes.11, 14, 15
This process can affect a small number of chromosomes or nearly the entire genome, resulting in the induction of genomic instability, formation of new genome systems, and providing material for genome-based cancer evolution. Owing to the associations between C-Frag, genomic instability, disease progression, and the intervention of chemotherapies, this work underscores the potential of using C-Frag as a diagnostic tool in clinical settings.