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- Gisselsson Nord, David, et al.
(author)
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Telomere-mediated mitotic disturbances in immortalized ovarian epithelial cells reproduce chromosomal losses and breakpoints from ovarian carcinoma
- 2005
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In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 42:1, s. 22-33
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Journal article (peer-reviewed)abstract
- Ovarian carcinomas (OCs) often exhibit highly complex cytogenetic changes. Abnormal chromosome segregation at mitosis is one potential mechanism for genomic rearrangements in tumors. In this study, OCs were demonstrated to have dysfunctional short telomeres, anaphase bridging, and multipolar mitoses with supernumerary centrosomes. When normal human ovarian surface epithelial (HOSE) cells were transfected with human papilloma virus 16 e6/e7 genes and subsequently driven into telomere crisis, the same set of mitotic disturbances occurred in a distinct sequence, initiated by telomere dysfunction, followed by anaphase bridging, and then supernumerary centrosomes and multipolar mitoses. The anaphase bridges resolved either by kinetochore-spindle detachment, corresponding to whole-chromosome losses in the HOSE karyotypes, or by extensive fragmentation of intercentromeric DNA sequences, corresponding to a high frequency of pericentromeric rearrangements. At later passages, the high degree of instability at telomere crisis was moderated by telomerase expression and centrosome coalescence, ultimately leading to a level of mitotic instability that was highly similar to that in OC cell lines and to complex karyotypes that were similar to those observed in high-grade OCs. This suggests that a significant proportion of the structural chromosome changes and genomic losses in OC are caused by a specific sequence of mitotic disturbances triggered by telomere crisis. That the model did not produce any of the whole-chromosome gains observed in OC indicates that these changes develop through a different mechanism.
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| 2. |
- Zhang, H, et al.
(author)
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Cytogenetic aberrations in immortalization of esophageal epithelial cells
- 2006
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In: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 165:1, s. 25-35
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Journal article (peer-reviewed)abstract
- To define the early cytogenetic events important in esophageal carcinogenesis, we immortalized normal esophageal epithelial cells by overexpression of human papillomavirus type 16 E6/E7 (HPV16E6/E7) and human telomerase reverse transcriptase (hTERT), and characterized the chromosomal abnormalities serially before and after Cellular immortalizaiton. During crisis. most cells had simple nonclonal karyotypic changes with cytogenetic divergence. Mitotically unstable chromosomes (i.e., telomere association and dicentric chromosomes) were the most common aberrations. After crisis, the karyotypic patterns were more convergent with nonrandom clonal changes. A few clones dominated the culture. Gain of chromosome 20q was consistently observed in four HPVE6/E7 immortalized esophageal lines, whereas amplification of chromosome 5q was preferentially found in hTERT immortalized cells. In addition, chromosomal aberrations of immortalized cells, including del(3p) and centromere rearrangements, were similar to those observed in esophageal cancer. Furthermore, in E6/E7-expressing cells, the frequency of negative telomere termini and anaphase bridges were high during crisis and low after crisis. These findings suggested that telomere dysfunction might be an important cause of cellular crisis, and the resultant chromosomal aberrations, mainly amplification of chromosome 20q or 5q, might be early genetic events required in esophageal cell immortalization. These alterations might be valuable models for further study of molecular mechanisms contributing to esophageal carcinogenesis. (c) 2006 Elsevier Inc. All rights reserved.
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