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First published online November 19, 2008
doi: 10.1242/10.1242/jcs.039537

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The consequences of tetraploidy and aneuploidy

Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany

View larger version (68K): [in this window] [in a new window]   Fig. 1. Distribution of chromosome number in common cancers. The percentage of tumors plotted against the corresponding maximum chromosome number reveals that diploid or near-diploid karyotypes dominate across cancer types. A high percentage of tumors with near-triploid or near-tetraploid chromosome numbers suggests that changes in whole chromosome sets are frequent in cancers. The Mitelman Database of Chromosome Aberrations in Cancers was used as a source of the data (http://cgap.nci.nih.gov/Chromosomes/Mitelman). The bracketed numbers indicate the number of tumors analyzed for each cancer.

View larger version (31K): [in this window] [in a new window]   Fig. 2. The three main roads to tetraploidy. Cell-cell fusion and failure of cytokinesis generate binucleated cells that contain two centrosomes. Binucleated cells can form mononucleated tetraploids after successful passage through the next mitosis. Mitotic slippage is a cellular adaptation to persistent mitotic arrest. Cells bypass anaphase, telophase and cytokinesis, and progress into the next G1 phase without correcting the mitotic error that triggered the arrest. Cells that are derived from mitotic slippage contain a single tetraploid nucleus that is accompanied by two centrosomes. 2N, diploid nucleus; 4N, tetraploid nucleus; 4C, diploid nucleus with replicated chromosomes.

View larger version (8K): [in this window] [in a new window]   Fig. 3. Defects associated with aberrant cell division can trigger cell death and might prevent proliferation of tetraploid cells. Defective kinetochores and microtubules (MTs), as well as disruption of centrosomes or the actin cytoskeleton, can initiate cell death. The mitotic-checkpoint proteins Bub1 and BubR1 might also trigger a post-mitotic, p53-dependent cell death after chromosome missegregation owing to spindle defects. The centrosomal kinase Lats2 inhibits p53 degradation by inhibiting Mdm2 in the absence of MTs, thus activating the apoptotic pathway. Disruption of centrosome integrity induces the p38 stress pathway, which can also trigger p53-dependent apoptosis. The experimental formation of tetraploid cells is frequently associated with disruption of the actin cytoskeleton. Cytoskeletal defects lead to disrupted focal adhesions, which, in their unimpaired state, are essential for cellular survival pathways because they can suppress the p38 stress pathway. p53 mediates apoptotic and cell-cycle-arresting signals by initiating the transcription of multiple effector proteins. It should be noted that the proposed pathways in this figure are not well established. For further details, see text.

View larger version (52K): [in this window] [in a new window]   Fig. 4. Centrosome amplification. Centrosome amplification can occur by at least four different mechanisms. (A) If the copy-number control fails (overduplication), e.g. owing to overexpression of polo-like kinase 4 (Plk4), several daughter centrioles are formed around one mother (flower formation). This leads to multiple centrosomes in the next cell cycle (Kleylein-Sohn et al., 2007). (B) Certain cancer cell lines, such as CHO or U2OS, duplicate their centrosomes more than once per cell cycle if kept in a prolonged S phase (reduplication) (Kuriyama et al., 2007). A similar effect can be observed in Xenopus laevis egg extracts arrested with an inhibitor of DNA synthesis (Hinchcliffe et al., 1999). (C) Pericentriolar material (PCM), the fibrous network surrounding centrioles, can fragment if the centrosomal structure is impaired by the inhibition, depletion or overexpression of centrosomal proteins. The acentriolar fragments can still serve as MTOCs and create multipolar spindles (Oshimori et al., 2006). (D) Tetraploid cells contain two centrosomes in G1 phase regardless of the mechanism of their formation. The centrosomes are duplicated in the subsequent S phase (e.g. Meraldi et al., 2002). 2C, diploid nucleus with unreplicated chromosomes; 4C, diploid nucleus with replicated chromosomes.

View larger version (25K): [in this window] [in a new window]   Fig. 5. Numerical CIN in various cancers. (A) Non-diploid tumors display CIN much more often than diploid tumors. The percentage of diploid (blue) and non-diploid (red) tumors with cell-to-cell variability in chromosome number has been plotted. Bracketed numbers indicate the number of tumors analyzed for diploid and non-diploid tumors, respectively. (B) Numerical CIN is less frequent in diploid and tetraploid tumors than in aneuploid tumors. The percentage of tumors with CIN is plotted against the average chromosome number. Every data point represents at least five tumors. The trend line represents the moving average in the second period (i.e. each point of the trend line represents the average of the two neighboring data points). The Mitelman Database of Chromosome Aberrations in Cancers was used as a source of the analyzed data (http://cgap.nci.nih.gov/Chromosomes/Mitelman).

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