Chromosomal instability and cytoskeletal defects in oral cancer cells

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2000; 97(1):303-8.
Source: PubMed


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-fusion-bridge 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.

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Available from: Susanne M Gollin, Feb 21, 2014
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    • "Acytokinetic tripolar mitosis has been proposed as a physiological mechanism of formation of trinucleate trophoblast giant cells in the bovine placenta (Klisch et al., 1999). Pathological occurrences include most cancers (Lingle et al., 2002; Ghadimi et al., 2000; Saunders et al., 2000), preneoplastic lesions (Chan, 2011), and various sick and infected cells (Mrak et al., 1995). Experimentally and therapeutically, tripolar mitosis can be induced by mitotic spindle toxins, some of them such as Paclitaxel or Vinblastine are used in chemotherapy (Demidenko et al., 2008; Speicher et al., 1992; reviewed by Chan et al., 2012), as well as by radiation doses such as those used in the treatment of tumors (Dodson et al., 2007). "
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    ABSTRACT: Tripolar mitosis is a specific case of cell division driven by typical molecular mechanisms of mitosis, but resulting in three daughter cells instead of the usual count of two. Other variants of multipolar mitosis show even more mitotic poles and are relatively rare. In nature, this phenomenon was frequently observed or suspected in multiple common cancers, infected cells, the placenta, and in early human embryos with impaired pregnancy-yielding potential. Artificial causes include radiation and various toxins. Here we combine several pieces of the most recent evidence for the existence of different types of multipolar mitosis in preimplantation embryos together with a detailed review of the literature. The related molecular and cellular mechanisms are discussed, including the regulation of centriole duplication, mitotic spindle biology, centromere functions, cell cycle checkpoints, mitotic autocorrection mechanisms, and the related complicating factors in healthy and affected cells, including post-mitotic cell-cell fusion often associated with multipolar cell division. Clinical relevance for oncology and embryo selection in assisted reproduction is also briefly discussed in this context. Copyright © 2014 Elsevier GmbH. All rights reserved.
    Acta Histochemica 12/2014; 100(1). DOI:10.1016/j.acthis.2014.11.009 · 1.71 Impact Factor
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    • "The precise molecular mechanisms that may cause CIN in tumor cells just recently became more evident. Studies aimed at identifying the mitotic defects that may be responsible for inducing chromosome mis-segregation in cancer cells (W-CIN) show that these defects include spindle assembly checkpoint (SAC) dysfunction, kinetochore attachment errors, mitotic spindle defects, and other cell division inaccuracies (50–60). There are many molecular defects leading to chromosomal mis-segregation in model systems, but which of them are present in cancer cells? "
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    ABSTRACT: Whole-chromosomal instability (W-CIN) - unequal chromosome distribution during cell division - is a characteristic feature of a majority of cancer cells distinguishing them from their normal counterparts. The precise molecular mechanisms that may cause mis-segregation of chromosomes in tumor cells just recently became more evident. The consequences of W-CIN are numerous and play a critical role in carcinogenesis. W-CIN mediates evolution of cancer cell population under selective pressure and can facilitate the accumulation of genetic changes that promote malignancy. It has both tumor-promoting and tumor-suppressive effects, and their balance could be beneficial or detrimental for carcinogenesis. The characterization of W-CIN as a complex multi-layered adaptive phenotype highlights the intra- and extracellular adaptations to the consequences of genome reshuffling. It also provides a framework for targeting aggressive chromosomally unstable cancers.
    Frontiers in Oncology 12/2013; 3:302. DOI:10.3389/fonc.2013.00302
    • "They also documented that epithelial cells from various sites of aerodigestive mucosa are not prone to or selected for the same type of genetic alteration following similar carcinogenic aggression. Breakage, fusion, and bridging cycles have been proposed to be an important mechanism of gene amplification.[12] "
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    ABSTRACT: Early diagnosis and appropriate management are of prime importance for oral squamous cell carcinoma (OSCC) in the present scenario. Molecular changes in OSCC are well documented with the occurrence of a wide range of genetic damage. Identification of the genetic damage in OSCC using various diagnostic aids is mandatory, and one of the important advances in this field is cytogenetics using fluorescence in-situ hybridization (FISH). The aim of the present study is to analyze the genetic alteration in OSCC using FISH as a diagnostic aid. Peripheral blood was analyzed in 20 clinically and histopathologically proven OSCC cases and 10 healthy controls for chromosomal alteration under standardized conditions. Of the 20 OSCC cases, 7 (35%) cases showed chromosomal alterations. No cases from the control group showed any chromosomal changes. Of the positive cases in OSCC, 30% cases showed increased copy number of cyclin D1 gene and 1 (5%) case showed positivity indicating extra copy of chromosome 11p11.11-q11 region. Increased genetic damage in OSCC which is a prominent feature can be identified by the use of FISH as seen from the present study. The findings suggest that FISH can be used as a diagnostic aid in the detection of genetic changes occurring in OSCC. The present study also suggests the importance of peripheral blood as a medium for assessing cytogenetic damage in OSCC.
    Journal of Oral and Maxillofacial Pathology 03/2013; 17(1):61-64. DOI:10.4103/0973-029X.110731
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