Cytokinesis defects and cancer

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Abstract

Whole-genome and centrosome duplication as a consequence of cytokinesis failure can drive tumorigenesis in experimental model systems. However, whether cytokinesis failure is in fact an important cause of human cancers has remained unclear. In this Review, we summarize evidence that whole-genome-doubling events are frequently observed in human cancers and discuss the contribution that cytokinesis defects can make to tumorigenesis. We provide an overview of the potential causes of cytokinesis failure and discuss how tetraploid cells that are generated through cytokinesis defects are used in cancer as a transitory state on the route to aneuploidy. Finally, we discuss how cytokinesis defects can facilitate genetic diversification within the tumour to promote cancer development and could constitute the path of least resistance in tumour evolution.

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Most cited references 176

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C Lengauer, K Kinzler, B Vogelstein (1998)

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

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Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu … (2012)

The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.

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F Bunz, A Dutriaux, C Lengauer … (1998)

After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.