What happens if mitosis does not work

How mitotic defects can act to promote tumor development remains an area of intense study. As a first path to facilitate tumorigenesis, CIN drives a continually evolving karyotype that produces genetic diversity in the tumor cell population.

In addition to population-level genetic variation, the dosage imbalances produced by aneuploidy have been shown to reduce the robustness of biological networks and increase cellular variability Beach et al.

Together, this genetic and nongenetic heterogeneity creates phenotypic diversity. While the vast majority of alterations to the karyotype is expected to be detrimental, a small fraction of those changes could be advantageous and selected for during tumor evolution.

The chromosomal location and relative density of tumor suppressor genes and oncogenes have been proposed to play an important role in shaping the tissue-specific patterns of aneuploidy observed in different types of cancer Davoli et al. A widely proposed mechanism by which mitotic errors facilitate tumor development is through the loss of a chromosome that contains the remaining wild-type copy of a tumor suppressor gene.

Indeed, this has been shown to occur in chromosomally unstable mice that were heterozygous for p53 or carried a mutated APC allele Baker et al. In addition to promoting primary tumor growth, recent work functionally linked CIN with metastasis by showing that chromosomally unstable tumor cell lines are more likely to spread and form new tumors when compared with the same cells in which CIN was suppressed Bakhoum et al.

Finally, the genetic instability produced by CIN could contribute to the evolution of resistance in response to targeted anti-cancer therapies. Genetically engineered mice that recapitulate the ongoing karyotype changes observed in the majority of human tumors are thus likely to represent powerful models for testing the efficacy of emerging clinical drug candidates.

The most extensive characterization of the role of mitotic errors in tumorigenesis has emerged from the development of mouse models that possess elevated or reduced levels of SAC proteins.

These animals display ongoing CIN and increased aneuploidy in cells and tissues. While many of these models are tumor-prone, some exhibit high levels of aneuploidy without an increase in tumor predisposition, demonstrating that the degree of aneuploidy is not an accurate predictor of tumor susceptibility Baker et al.

One possible explanation for this observation is that some of the proteins that are manipulated have functions outside of mitosis that confound interpretations of the tumor phenotypes Funk et al.

For example, SAC proteins have been proposed to play roles in insulin signaling Choi et al. An alternative possibility is that the genes manipulated to induce chromosome missegregation lead to distinct types of mitotic errors that change the karyotype in different ways. On the other hand, overexpression of MAD2 produces lagging anaphase chromosomes that can be subjected to DNA double-strand breaks and serve as a source of chromosomal rearrangements Sotillo et al.

It will be interesting to determine to what extent the frequency of DNA breaks that result from mitotic errors correlates with the propensity for tumor development. Although considerable effort has been focused on modeling mitotic errors using mice with altered levels of SAC components, SAC dysfunction does not appear to be a major driver of CIN in human tumors.

Given the established role of centrosome amplification in promoting CIN and its widespread presence in aneuploid human tumors, recent attention has turned to generating mice in which extra centrosomes could be generated by overexpressing PLK4, the master regulator of centrosome biogenesis Marthiens et al. Modest overexpression of Plk4 produced chronic centrosome amplification and aneuploidy in multiple tissues and was sufficient to drive the formation of lymphomas and squamous cell carcinomas Levine et al.

Strikingly, these tumors exhibited high levels of aneuploidy, ongoing chromosome segregation errors, and defective p53 signaling. Furthermore, tumors that formed as a result of centrosome amplification exhibited complex karyotypes that mimicked those frequently found in human tumors.

It will now be valuable to develop additional animal models that mimic other mitotic aberrations frequently observed in human tumor cells, such as hyperstabilized K—MT interactions. Although mitotic errors have long been implicated in driving cancer, it is becoming clear that in some contexts, increasing chromosome segregation errors can act to suppress tumorigenesis. Indeed, combining low rates of chromosome missegregation from expression of a mutant APC allele with additional CIN from reduced levels of CENP-E resulted in increased cell death that suppressed tumor progression but not initiation Zasadil et al.

This suggests that low rates of chromosome missegregation can promote tumor development, while high levels of CIN lead to the loss of essential chromosomes and tumor suppression Funk et al.

This explains the seemingly paradoxical observation that low levels of CIN are associated with a poor outcome in estrogen receptor-negative breast cancer, while high levels of CIN correlate with improved long-term survival Birkbak et al. Since excessive chromosome segregation errors are lethal, tumors may select for alterations that antagonize the effects of excessive CIN.

Therefore, increasing the duration of mitosis could be a strategy used by cancer cells to tune the level of CIN and counteract the long-term fitness defects caused by excessive chromosome segregation errors. Consistently, single-cell genome sequencing of human breast tumors revealed that aneuploidy occurs early during tumor evolution but remains relatively stable during tumor outgrowth Wang et al.

This suggests that once a critical point has been reached, increased genome stability can be selected for to aid tumor growth. Taken together, the available data suggest that mitotic errors can have distinct impacts at different points during tumor development.

Low rates of mitotic errors can be tumor-promoting, particularly in the context of inactivating pathways that suppress the growth of aneuploid or polyploid cells.

Nevertheless, higher rates of chromosome segregation errors lead to loss of essential chromosomes and tumor suppression. Identifying genetic alterations that cooperate to facilitate the transformation of chromosomally unstable cells is an important area of future work. It has been appreciated since the s that the immune system can recognize tumor antigens and eliminate nascent tumor cells Bose These findings have spurred the development of immunotherapies that act to stimulate the immune system's ability to attack cancer cells that evolve to evade immune recognition.

A compelling body of new experimental data supports the notion that the immune system can recognize and eliminate cells with complex karyotypes, raising the question of how these alterations are detected and how they contribute to shaping tumor evolution and therapeutic responses. Cancer cells with abnormal karyotypes can emit signals that serve to increase their immunogenicity. One major signal is driven by the constitutive endoplasmic reticulum stress in aneuploid cells that leads to an increased exposure of immunogenic cell surface molecules and subsequent clearance by innate and adaptive immune cells Fig.

The second messenger cGAMP binds and activates STING stimulator of interferon genes , leading to the production of type I interferon and other proinflammatory cytokines that trigger the immune response Fig.

Intracellular cGAMP can spread to neighboring cells through gap junctions to rapidly produce a paracrine proinflammatory signaling program Ablasser et al. Mitotic errors activate the immune system. A Aneuploid cells exhibit a constitutive endoplasmic reticulum ER stress that leads to the increased surface exposure of immunogenic cell surface molecules, such as calreticulin.

These are recognized by immune cells such as natural killer NK cells, dendritic cells, macrophages, and T cells that engulf or kill the aneuploid cell. B The micronuclear envelope is prone to rupture, leading to the exposure of the entrapped chromatin to cytoplasmic DNA-sensing molecules, such as cGAS. Mitotic errors can cause whole chromosomes or parts of chromosomes to be partitioned into micronuclei.

As discussed previously, chromosomes contained within micronuclei are subject to massive chromosome fragmentation following the spontaneous rupture of the micronuclear membrane Crasta et al. Micronuclear rupture may also release DNA fragments into the cytosol, explaining why chromosomally unstable cells have high levels of cytosolic DNA Bakhoum and Landau Accordingly, inflammatory signals are up-regulated in cells with micronuclei generated by ionizing radiation Mackenzie et al.

DNA breaks that persist in mitosis lead to the generation of chromosome fragments that lack centromeres and cannot be segregated. These chromatin fragments escape from the nucleus and result in the formation of micronuclei in the next cell cycle. Senescence is an irreversible growth arrest brought about by stresses such as ionizing radiation, oncogene activation, or persistent DNA damage Tchkonia et al. Arrested aneuploid cells have been shown to exhibit senescent characteristics and produce a SASP-like gene expression signature in vitro Santaguida et al.

These aneuploid cells also display increased expression of natural killer NK cell-activating ligands and are efficiently eliminated when cocultured with NK cells in vitro Fig. Future work will focus on determining the importance of micronucleus- or senescence-induced cytosolic chromatin for triggering activation of cGAS—STING in aneuploid cells.

Moreover, it remains to be established how effectively these pathways act to promote the immune clearance of aneuploid cells in vivo. Taken together, the evidence suggests that recognition of cancer cells by the immune system can be mediated by an aneuploid state or alterations associated with it. Tumor cells with complex karyotypes must thus evolve mechanisms to suppress recognition by the immune system.

Accordingly, chromosomally unstable tumor cell lines avoid induction of proinflammatory signaling despite high levels of cytosolic DNA Bakhoum and Landau Moreover, analysis of tumors from The Cancer Genome Atlas data sets revealed that cancers with highly aneuploid karyotypes exhibited reduced expression of genes related to cytotoxic immune functions and the production of proinflammatory cytokines Buccitelli et al.

A retrospective study of melanoma patients treated with immune checkpoint blockade anti-CTLA4 therapy showed that those with low levels of aneuploidy responded better. These data support the idea that the microenvironment of karyotypically deranged tumors is immunosuppressive and suggest that evaluating the levels of tumor aneuploidy could be used to predict responsiveness to immunotherapy. Genetic alterations that enhance resistance to the host immune system have been identified in cancers Khong and Restifo Therefore, identifying whether this or other mechanisms are responsible for the reduced immunogenicity of highly aneuploid tumors is an important area of future work that could offer insights into how to improve patient responsiveness to immunotherapy.

Given the widespread prevalence of mitotic errors in human cancers, several approaches have been explored to target the mitotic apparatus or exploit weaknesses associated with the aneuploid state. With a long history of clinical efficacy, MT targeting agents are the most widely used anti-cancer drugs that target cell division. One of the most successful drugs in this class is paclitaxel, which has been used for decades to treat breast, ovarian, and lung cancer.

Paclitaxel binds and stabilizes the MT lattice and, at high concentrations, arrests dividing cells in mitosis by preventing silencing of the SAC, leading to either cell death or senescence.

However, clinically relevant doses of paclitaxel do not generate a mitotic arrest but rather lead to the formation of multipolar spindles that induce massive chromosome missegregation and cell death Symmans et al. While killing of dividing cells is an attractive model for the anti-tumor actions of paclitaxel, this mechanism is difficult to reconcile with the slow proliferation rate of many solid tumors, which predicts that too few cells progress through mitosis in the presence of the drug to account for broad tumor killing Mitchison In this model, micronucleation in a subset of cells that passes through mitosis in the presence of paclitaxel produces a proinflammatory signal that leads to en masse killing of tumor cells.

While this proposal remains to be tested, it has the attractive feature of explaining why paclitaxel is more effective at killing solid tumors than other drugs that target the mitotic apparatus but do not induce micronucleation. The clinical success of paclitaxel spurred the development of multiple mitotic-specific drugs that target enzymes required for cell division Dominguez-Brauer et al. These drugs override the mitotic checkpoint and increase the frequency of chromosome segregation errors, leading to the generation of inviable karyotypes.

Excitingly, MPS1 inhibitors have been found to sensitize xenograft tumors to paclitaxel-induced killing by elevating the chromosome segregation errors above a threshold required for viability Jemaa et al. However, despite promising preclinical results, mitosis-specific drugs have shown limited efficacy in clinical trials and in most cases are outperformed by classic MT targeting agents such as paclitaxel Komlodi-Pasztor et al. One reason for this discrepancy is likely to be the slow proliferation rate of tumors in vivo compared with cancer cell lines and xenograft tumors on which the drugs were tested Komlodi-Pasztor et al.

An additional barrier limiting the success of mitotic-specific drugs is their inability to discriminate between the divisions of normal cells and tumor cells, resulting in bone marrow toxicity that limits the dose and duration of treatment.

Next-generation mitosis-specific drugs are likely to be more successful if they exploit tumor-specific vulnerabilities. One example of such an approach is to target the divisions of cancer cells with extra centrosomes. Since cancer cells efficiently cluster extra centrosomes to avoid lethal multipolar divisions, inhibiting the pathways required for centrosome clustering will selectively destroy cells with extra centrosomes without affecting the growth of normal cells.

HSET is not required for the growth of cells with the normal number of centrosomes but is required for the viability of tumor cells with extra centrosomes. This knowledge has sparked the development of a suite of new drugs that aim to destroy tumor cells with extra centrosomes by suppressing centrosome clustering Rebacz et al. While these compounds have been shown to decluster centrosomes and induce lethal multipolar divisions in cell culture, whether these tumor-specific drugs achieve an enhanced therapeutic index and improved clinical efficacy remains to be determined.

In addition to targeting the cell division machinery, it may also be possible to expose the consequence of cell division errors by exploiting vulnerabilities associated with the aneuploid state itself. Aneuploid cells are more sensitive than euploid cells to compounds that exacerbate proteotoxic stress and metabolic stress Tang et al.

Moreover, pharmacological activation of both of these stress pathways acts synergistically to suppress the growth of chromosomally unstable xenograft tumors. Aneuploid cells also exhibit dysregulated sphingolipid metabolism that leads to increased levels of the proapoptotic lipid ceramide Hwang et al. Correspondingly, pharmacological agents that increase ceramide levels are more toxic to aneuploid cells than diploid cells Tang et al.

Together, these studies offer a proof of principle that the aneuploid state can be exploited therapeutically and open the door to the possibility of generating broad-spectrum anti-cancer drugs that aim to exacerbate stresses inherent to aneuploid cells.

Research into the basic mechanisms underlying faithful chromosome segregation has revealed insights into how mitotic errors contribute to intratumor heterogeneity, tumor progression, metastasis, and adaptive evolution in response to therapy. However, we still lack an in-depth understanding of the long-term impact of cell division errors in vivo. In the future, animal models that recapitulate the molecular defects responsible for promoting mitotic errors in human cancers will be instrumental in elucidating the physiological consequences of cell division errors and their impact on tumorigenesis.

Such animal models will also aid in understanding the emerging link between cell division errors and the activation of the immune system. In particular, it remains unclear how effectively aneuploid cells are recognized and cleared by the immune system in vivo. Moreover, whether the proinflammatory consequences of cell division errors drive the evolution of an immunosuppressive tumor microenvironment remains to be tested. The development of methodologies for evaluating the rates of cell division errors in vivo will be critical if they are to be leveraged for therapeutic intervention.

It will therefore be important to move away from using FISH and metaphase spreads to measure aneuploidy and instead turn to more reliable and higher-resolution single-cell sequencing to evaluate karyotype changes. We will also benefit from further insight into how p53 is activated following cell division errors and how tumor cells evolve mutations to tune the rate of CIN.

Understanding the impact of cell division errors on cellular physiology holds great promise for our understanding and treatment of cancer. In this regard, exploiting molecular differences in the ways that normal and tumor cells divide to selectively target the division of cancer cells is a particularly promising therapeutic avenue.

We thank our laboratory members for helpful discussions and apologize to colleagues whose work could not be cited due to space limitations. View all The impact of mitotic errors on cell proliferation and tumorigenesis Michelle S. Levine and Andrew J. Previous Section Next Section. Spindle assembly checkpoint SAC defects The objective of mitosis is to faithfully segregate the replicated chromosomes into two new daughter cells.

Figure 1. Cohesion defects The separation of the chromosomes at anaphase relies on the timely loss of sister cohesion Fig. Centrosome amplification A further source of merotelic attachments arises from the acquisition of extra copies of the centrosome, known as centrosome amplification Fig.

Timing of centrosome separation The improper timing of centrosome separation prior to cell division is emerging as an additional source of genetic instability Nam et al. Tetraploidy A final source of mitotic errors arises from the proliferation of tetraploid cells, which have twice the normal chromosome content.

Mitotic errors lead to DNA damage Mitotic errors have long been recognized to be a major source of whole-chromosomal aneuploidy, but recent evidence has also linked chromosome segregation errors to the generation of DNA damage that promotes structural alterations in chromosomes. Figure 2. Mitotic errors can trigger activation of p53 In studying the immediate effects of cell division errors on cellular proliferation, a common theme has emerged: Mistakes in cell division frequently lead to activation of the tumor suppressor protein p53, which in turn induces a cell cycle arrest, senescence, or apoptosis.

Figure 3. Aneuploidy can promote further genome instability Mitosis is a dynamic and finely tuned event that is particularly sensitive to perturbations in gene expression arising from karyotype alterations. Figure 4. Previous Section. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.

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Cells have ways of ensuring that mitosis does not go wrong, but when these safeguards fail, faulty mitosis produces mutant cells. Mitosis is a multi-step process with checkpoints to make sure things are going properly. If a cell detects that something has gone wrong during mitosis, the first thing it does is to stop the process.

The three major checkpoints during mitosis -- the G1, G2 and mitotic spindle checkpoints -- all provide the cell with an opportunity to intervene if something goes wrong so that it can fix the problem.

Each checkpoint is policed by specific proteins that ensure that everything is working properly. During mitosis, the DNA within the cell duplicates. The process involves many changes and the movement of chromosomes -- which carry the DNA -- and organelles within the cell. This activity can sometimes cause DNA to break.

A protein called p53, otherwise known as the "guardian of the genome," is a key sensor of DNA damage in animal cells. After detecting damage, it causes the cell cycle to stop, which allows time for repairs. Other chapters in Help Me Understand Genetics. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

How do cells divide? From Genetics Home Reference. Mitosis and meiosis, the two types of cell division.