Chromosomal instability and cytoskeletal defects in oral cancer cells

Abstract

Oral squamous cell carcinomas are characterized by complex, often near-triploid karyotypes with structural and numerical variations superimposed on the initial clonal chromosomal alterations. We used immunohistochemistry combined with classical cytogenetic analysis and spectral karyotyping to investigate the chromosomal segregation defects in cultured oral squamous cell carcinoma cells. During division, these cells frequently exhibit lagging chromosomes at both metaphase and anaphase, suggesting defects in the mitotic apparatus or kinetochore. Dicentric anaphase chromatin bridges and structurally altered chromosomes with consistent long arms and variable short arms, as well as the presence of gene amplification, suggested the occurrence of breakage-fusionbridge cycles. Some anaphase bridges were observed to persist into telophase, resulting in chromosomal exclusion from the reforming nucleus and micronucleus formation. Multipolar spindles were found to various degrees in the oral squamous cell carcinoma lines. In the multipolar spindles, the poles demonstrated different levels of chromosomal capture and alignment, indicating functional differences between the poles. Some spindle poles showed premature splitting of centrosomal material, a precursor to full separation of the microtubule organizing centers. These results indicate that some of the chromosomal instability observed within these cancer cells might be the result of cytoskeletal defects and breakage-fusion-bridge cycles.

Chromosomal imbalances in oral squamous cell carcinoma: Examination of 31 cell lines and review of the literature

“…Despite the observation that individual OSCC tumor cells express unique karyotypes and at times unique numerical and structural aberrations, many abnormalities within and among malignant cell populations appear to be clonal and remain constant over time in spite of chromosomal instability resulting from chromosome segregation defects. 95 This suggests that clonal abnormalities provide a selective growth advantage for high grade tumors, consistent with the suggestion by Albertson et al. 96 Our cell lines have been examined in our laboratory as late as passage 68 and appear to be remarkably stable.…”

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

“…Chromosomal bridging in fission yeast is a consequence of compromised kinetochore function (Ekwall et al, 1999) whereas in mammalian cells, it may arise from telomere defects, abnormalities in DNA replication and/or recombination, translocations associated with bi-centromeric chromosomes or overexpression of mitotic checkpoint genes (Harley and Villeponteau, 1995;Menssen et al, 2007;Sotillo et al, 2007). Chromosomal bridging has also been implicated in the creation of micronuclei similar to those reported here ( Figure 5; Saunders et al, 2000) and leads to other structural and numerical abnormalities (Saunders, 2003). Together with previous studies showing that inhibition of cytokinesis in p53À/À mammary epithelial cells leads to the appearance of bi-nucleated cells that are structurally indistinguishable from those of p53 þ / þ cells (Fujiwara et al, 2005), our current findings argue that p53 serves to inhibit or eliminate cells whose genomes have been altered as a result of GpIba overexpression.…”

Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres

“…This phenomenon has recently been described in several tumour types, including pancreatic and ovarian adenocarcinoma, HNSCC (Gisselsson et al, 2000;Saunders et al, 2000), osteosarcoma, and soft tissue sarcoma (Gisselsson et al, 1999). Such bridges may consist of mitotically unstable chromosomes undergoing repeated breakage-fusion-bridge (BFB) cycles, Figure 3 Multiple centrosomes (g-tubulin, red) in mononucleated (A), binucleated (B), and pentanucleated cells (C) in cases 1, 2, and 8, respectively.…”

“…Mitotic instability including breakage and/or nondisjunction of chromosomes has been demonstrated in established cell lines from HNSCC (Saunders et al, 2000). Recently, it has been suggested that this type of chromosome instability could be triggered by telomere dysfunction, leading to instability of chromosome termini Gisselsson et al, 2001b).…”

“…Recently, it has been suggested that this type of chromosome instability could be triggered by telomere dysfunction, leading to instability of chromosome termini Gisselsson et al, 2001b). Another mode of mitotic instability found in HNSCC cell lines consists of multipolar cell divisions, possibly caused by supernumerary centrosomes (Saunders et al, 2000). Little is known about the relation between centrosome abnormalities and mitotic multipolarity, on the one hand, and telomeric dysfunction and mitotic chromosome breakage on the other.…”