Proposed Model (IMAGE)
Caption
Proposed model of the hyperploid pathway as a salvage survival strategy regulated by the G2-M checkpoint. Hyperploid pathway as a salvage survival strategy after moderate to high but not extreme concentration of platinum treatment (i.e. 20-100 uM). After platinum treatment, the activation of the G2-M cell cycle checkpoint led to the initial arrest of tumor cells at the G2-phase for DNA damage repair. Under the traditional regeneration pathway, tumor cells that did not perform sufficient DNA damage repair would undergo cell death such as by apoptosis or necrosis whereas others that achieved higher level of repair would eventually emerge from the G2 arrest and progress through mitosis to produce viable daughter cells. These normal progenies would predominantly contribute to the regeneration of the tumor cell line. However, an alternate salvage survival pathway was observed in which some of the initially G2-arrested tumor cells with residual DNA damage burden could avoid apoptotic cell death and aberrantly progress through mitosis at an intermediate to late time point. The perilous entry into mitosis while carrying residual DNA damage led mostly to mitotic catastrophe cell death. But there were occasional tumor cells that managed to exit mitosis via mitotic slippage and thereby avoided mitotic death. Following mitotic slippage, subsequent less-defined processes thought to result in the duplication of the genome led these cells to a hyperploid state. Although these de novo generated hyperploid tumor cells may continue to persist in this state, some may die while a substantial fraction would undergo mitosis. The chance for successful mitotic completion depended critically on the initial platinum treatment concentration and only those that were derived from the lowest treatment concentration could produce viable progenies. It remains to be further explored whether and how these unique progenies would contribute to the diversity of the regenerating tumor cell line.
Credit
Correspondence to - Robert Rottapel - rottapel@uhnresearch.ca and Andras Kapus - andras.kapus@unityhealth.to
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