Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity - PubMed (original) (raw)

Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity

Ylva Stewénius et al. Proc Natl Acad Sci U S A. 2005.

Abstract

Telomere dysfunction has been associated with chromosomal instability in colorectal carcinoma, but the consequences of telomere-dependent instability for chromosome integrity and clonal evolution have been little explored. We show here that abnormally short telomeres lead to a wide spectrum of mitotic disturbances in colorectal cancer cell lines, including anaphase bridging, whole-chromosome lagging, and mitotic multipolarity. These abnormalities were found in both the presence and absence of microsatellite instability. The mean telomere length varied extensively between cells from the same tumor, allowing the establishment of tumor cell subpopulations with highly different frequencies of mitotic disturbances. Anaphase bridging typically resulted in either inter-centromeric chromatin fragmentation or centromere detachment, leading to pericentromeric chromosome rearrangements and loss of whole chromosomes, respectively. There was a strong correlation between anaphase bridges and multipolar mitoses, and the induction of dicentric chromosomes by gamma irradiation and telomerase inhibition led to an elevated frequency of multipolar mitotic spindles, suggesting that multipolarity could result from polyploidization triggered by anaphase bridging. Chromatid segregation in multipolar mitoses was close to random, resulting in frequent nullisomies and nonviable daughter cells. In contrast, there was a high clonogenic survival among cells having gone through anaphase bridging in bipolar mitoses. Bridging of telomere-deficient chromosomes could thus be a major mutational mechanism in colorectal cancer, whereas mitotic multipolarity appears to be a secondary phenomenon that rarely, if ever, contributes to clonal evolution.

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Figures

Fig. 1.

Fig. 1.

Cytogenetic analyses and single-cell cloning. (A) TTAGGG-negative ends (red arrows) and a dicentric chromosome (green arrow) in SW480. (B and C) Anaphase bridges in DLD1 (B) and SW480 (C). (D) Loss of chromosomes X (arrow; centromere in green) and 18 (centromere in violet) through bridge formation in SW480. (E and F) Fragmented DNA (green) flanked by alphoid repeats (arrows; red) in SW480. (G and H) A dicentric chromosome 7 derivative (red chromosome paint in G; red arrow in H) and two normal chromosomes 12 (green chromosome paint in G) in HT29. (I) A ring chromosome positive with the 7q31 probe (green) but not with the chromosome 7 alphoid probe (red) in the HCT116 subclone M7. (J and K) A tetrapolar anaphase cell in hematoxylin-eosin staining (J) and a tripolar metaphase cell with three centrosomes (K)(γ-tubulin in orange) in SW480. (L_–_N) FISH analyses with centromeric probes in SW480 showing a tetrapolar metaphase cell with four copies of the X chromosome (green) and six copies of chromosome 18 (violet) (L), a tripolar anaphase cell with 2 + 2 + 0 segregation of chromosome X and 3 + 2 + 1 segregation of chromosome 18 (M), and a tripolar anaphase cell with 3 + 1 + 0 segregation of chromosome 18 (N). (O) Degenerating daughter cells of an isolated tetrapolar mitotic cell from the same cell line. (Magnifications: ×1,000, A, E, and I; ×100, B_–_D, F, and J_–_N; ×2,000, G and H; and ×40, O.)

Fig. 2.

Fig. 2.

Telomere lengths, postirradiation development, and aneusomy. (A) Mean TFI measurements in normal lymphocytes and cells from three colorectal carcinoma cell lines; x axis represents rank order of cells. (B) Frequencies of cells with anaphase bridges before (passage 0) and after (passages 1–6) gamma irradiation of HCT116 cells with WT TP53 status and SW480 cells with homozygous TP53 mutation. (C) Interphase FISH assessment of the frequency of aneusomic cells using centromeric (cen) probes. (D) Frequencies of MMs before (passage 0) and after irradiation (passages 1–6) of HCT116 and SW480 cells.

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