The Causes and Consequences of Polyploidy in Normal Development and Cancer

Davoli, Teresa; Lange, Titia de

doi:10.1146/annurev-cellbio-092910-154234

Cited by 388 publications

(445 citation statements)

References 171 publications

(150 reference statements)

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“…Trophoblast giant cells, which constitute the placenta, and megakaryocytes, the precursors of platelets, are also polyploid. However, in these two cases, and indeed in cases in other organisms, polyploidy is associated with a terminally differentiated state and cell cycle arrest (32). Hepatocytes are an exception to this rule.…”

Section: Discussionmentioning

confidence: 94%

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

284

253

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Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.

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Section: Discussionmentioning

confidence: 94%

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

284

253

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“…2A and B). Polyploidy results from subsequent cycles of DNA replication in the absence of cytokinesis and is associated with mitotic checkpoint defects (29). The minimal amount of BMS-777607 required to induce polyploidy is at 1 mmol/L for both T-47D and ZR-75-1 cells ( Fig To determine whether RON expression is required for BMS-777607-induced polyploidy, we compared the effect of compared BMS-777607 with CP-I and PHA665752 on polyploidy induction.…”

Section: Induction Of Polyploidy By Bms-777607 In Breast Cancer Cellsmentioning

confidence: 99%

“…Cells were then extensively washed and allowed to enter mitosis in the absence of BMS-777607. Control T-47D cells were synchronized at the G 2 -M border by pre-incubation for 24 hours with 5 mmol/L R0-3306, a Cdk1 inhibitor (29). Treatment of cells with R0-3306 for up to 24 hours caused a fully reversible G 2 -M cell-cycle arrest (29).…”

Section: Disruptive Effect Of Bms-777607 On Cellular Mitotic Spindle mentioning

confidence: 99%

Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

Sharma

Zeng

Zhuang

et al. 2013

Molecular Cancer Therapeutics

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The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here, we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of a-tubulin and g-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bipolar spindle formation and causes multipolar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607-treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells toward chemotherapeutics. Treatment with doxorubicin, bleomycin, methotrexate, and paclitaxel significantly increased cellular IC 50 values. These findings highlight the theory that BMS-777607 acts as a multikinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607. Mol Cancer Ther; 12(5); 725-36. Ó2013 AACR.

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“…A supraphysiological frequency of tetraploid cells has been detected at early stages of multiple cancer cell types (including bronchial, esophageal, gastric, mammary, colorectal, ovarian, cervical, and prostate carcinomas), often correlating with the inactivation of the tumor suppressors retinoblastoma 1 (RB1) and tumor protein p53 (TP53, best known as p53) (7). The inactivation of p53 facilitates the tetraploidization of cell lines (8)(9)(10) and primary epithelial cells from the colon and the mammary gland (11)(12)(13).…”

mentioning

confidence: 99%

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

Lissa

Senovilla

Rello-Varona

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc Min/+ mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

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The Causes and Consequences of Polyploidy in Normal Development and Cancer

Cited by 388 publications

References 171 publications

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

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