Subpopulations of tumor cells may exhibit diverging behaviors from the bulk tumor due to an alternate stress response that diverts tumor cells from apoptotic death.
In this study, the researcher identified a salvage survival pathway in which G2-arrested tumor cells bypassed apoptosis and progressed through aberrant mitotic events to then emerge as a distinct subpopulation of viable large hyperploid cells but with uncertain long-term propagation potential.
Dr. Robert Rottapel and Dr. Andras Kapus said "High grade serous carcinoma (HGSC) of tubal-ovarian origin is an aggressive epithelial tumor with poor survival outcomes. Platinum drugs are used as part of first-line therapy and exert genotoxic effects to tumor cells"
For tumor cells lacking a functional G1-S checkpoint such as in high grade serous carcinoma where the retinoblastoma and p53 pathways are perturbed, an arrest in cell cycle at the G2 phase is critical for DNA damage repair.
The entry to mitosis with residual DNA damage often results in mitotic catastrophe-mediated cell death but occasional tumor cells may circumvent mitotic death by failure to complete telekinesis and revert back to a single cell state termed mitotic slippage .
While chemotherapy treatment induces apoptotic cell death in the tumor, there are additional morphologic changes within the treated tumor field that suggest alternate mode of cell death or occasional survival via non-canonical response to treatment.
The cell cycle and DNA ploidy status are then additionally correlated with markers of key cellular programs such as the DNA damage response and G2-M cell cycle checkpoint pathway via immunofluorescence staining.
As this approach analyzes all tumor cells within a population at the single cell level, distinct subpopulational responses to treatment within the bulk tumor cell line can be revealed.
Using this refined technical approach, here we demonstrate that platinum treatment induces nuclear enlargement in the surviving cell population of several HGSC cell line models, and this in-vitro observation resembles closely to the morphologic changes seen in-vivo in patient tumors after neoadjuvant chemotherapy treatment.
The Rottapel/Kapus Research Team concluded, "The efficacy of this pathway to produce viable progenies was low and highly contingent on the initial platinum concentration that generated the hyperploid cells.
Potentially, the coupled process of hyperploidization and de-polyploidization might increase the genomic diversity of the recovering tumor cell line and contribute to acquired platinum resistance."
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