Abstract
The chromosomal instability of polyploid cells, which leads to the formation of aneuploid cells, is causally related to carcinogenesis in human tissues. However, the precise link between the chromosomal instability of polyploid cells and oncogenic transformation of them remains elusive. This is partly because we lack an experimental model in which non-transformed polyploid human cells can propagate in vitro. In a previous report, we demonstrated that proliferative tetraploid cells can be established from TIG-1 human fibroblasts by treatment with the spindle poison demecolcine (DC, colcemid) for 4 days. However, this procedure could not be applied to other human fibroblast strains because the resulting cells proliferated as a mixture of diploid and tetraploid populations. Here, we report a modified procedure to establish proliferative tetraploid cells from human fibroblasts of the BJ strain with minimum contamination by diploid cells. In the modified procedure, DC-arrested mitotic cells were collected by mitotic shake-off and treated with DC for an additional 3 days. DC-treated cells restarted proliferation as tetraploid cells after several days of growth arrest and showed similar growth to that of untreated diploid cells. The MDM2 antagonist Nutlin-3a activated p53 in established tetraploid cells and suppressed their growth, indicating that these cells have functional p53. These results contradicted the hypothesis that p53 functions as the tetraploidy checkpoint and prevents proliferation of tetraploid cells. Tetraploid cells established by our method could be a valuable model for the study of chromosomal instability and the oncogenic potential of polyploid cells.
Highlights
In the early stages of human carcinogenesis, polyploid cells often arise and form preneoplastic lesions that give rise to malignant aneuploid cells
We demonstrated that proliferative tetraploid cells can be established fromTIG-1 human fibroblasts by treatment with the spindle poison demecolcine (DC, colcemid) for 4 days
Near-diploid aneuploidy is prevalent in tumors and polyploidy is not the only route to generate aneuploid cells [1], recent research suggests that the formation of polyploid cells and their chromosomal instability appear to be causally related to human carcinogenesis
Summary
In the early stages of human carcinogenesis, polyploid (mostly tetraploid) cells often arise and form preneoplastic lesions that give rise to malignant aneuploid cells. Near-diploid aneuploidy is prevalent in tumors and polyploidy is not the only route to generate aneuploid cells [1], recent research suggests that the formation of polyploid cells and their chromosomal instability appear to be causally related to human carcinogenesis. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis and predispose cervical cells to aneuploidy [4, 5]. The precise relationship between the chromosomal instability of polyploid cells and oncogenic transformation remains elusive. This is partly because we lack a suitable experimental model in which non-transformed polyploid human cells can propagate in vitro
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