Linking Unfolded Protein Response to Ovarian Cancer Cell Fusion

Abstract

Background: Polyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors. They can resist antimitotic drugs, thus participating in tumor maintenance and recurrence. Despite their origin remains unclear, PGCC formation seems to be enhanced by conditions that trigger the unfolded protein response (UPR) such as hypoxia or chemotherapeutic treatments. Hypoxia has been shown to promote the formation of ovarian PGCCs by cell fusion. These PGCCs can undergo bursting and budding, contributing to generate cancer stem-like cells with more aggressive phenotypes than the parental cells.Methods: The UPR was induced in two ovarian cancer cell lines (SKOV3 and COV318). UPR activation was assessed by western blot and polyploidy indexes were calculated. Then, to confirm the implication of cell fusion in PGCCs formation, two populations of SKOV3 cells were transfected with plasmids encoding for two distinct nuclear fluorescent proteins (GFP and mCherry) associated with different antibiotic resistance genes, and the two cell populations were mixed in co-culture. The co-culture was submitted to a double-antibiotic selection. The resulting cell population was characterized for its morphology, cyclicity, and proliferative and tumorigenic capacities, in addition to a transcriptomic characterization.Results: We demonstrated that cell fusion could be involved in ovarian PGCCs generation and this process was promoted by unfolded protein response activation. Double-antibiotic treatment of PGCCs led to the selection of a pure population of cells containing both GFP- and mCherry-positive nuclei. Interestingly, after three weeks of selection, we observed that these cells were no longer polynucleated but displayed single nucleus positive for both fluorescent proteins, suggesting that genetic material mixing had occurred. These cells had restarted normal cell cycles, acquired an increased invasive capacity, and can form ovarian tumors in ovo.Conclusions: UPR activation increased the in vitro formation of PGCCs by cell fusion, further leading to the acquisition of new properties for the newly generated cells. UPR modulation in ovarian cancer patients could be an interesting therapeutic strategy to avoid the formation of PGCCs and therefore limit cancer relapse and drug resistance.

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“…[32] At the same time, hypoxia leads to apoptosis inhibition of tumor cells, and apoptosis induction is one of the important mechanisms of chemotherapeutic drugs, so hypoxia can increase chemotherapeutic resistance. [33] Viallard and Larrivée [34] and others researchers described the relationship between the abnormal tumor angiogenesis and tumor microenvironment. The morphology and structure of tumor neovascularization become highly disordered under the continuous action of angiogenic factors such as VEGF.…”