Abstract
To understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs following treatment with paclitaxel in ovarian cancer cells. An acute activation of IL-6 dominated senescence-associated secretory phenotype lasted 2–3 weeks and declined during the termination phase of polyploidy. IL-6 activates embryonic stemness during the initiation of PGCCs and can reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) via increased collagen synthesis, activation of VEGF expression, and enrichment of CAFs and the GPR77 + /CD10 + fibroblast subpopulation. Blocking the IL-6 feedback loop with tocilizumab or apigenin prevented PGCC formation, attenuated embryonic stemness and the CAF phenotype, and inhibited tumor growth in a patient-derived xenograft high-grade serous ovarian carcinoma model. Thus, IL-6 derived by PGCCs is capable of reprogramming both cancer and stromal cells and contributes to the evolution and remodeling of cancer. Targeting IL-6 in PGCCs may represent a novel approach to combating drug resistance.
Highlights
Most deaths from ovarian cancer occur as a result of treatment resistance and relapse following chemotherapy [1,2,3]
Treatment with paclitaxel led to mitotic crisis and massive cell death; it led to the formation of Polyploid giant cancer cells (PGCCs) (Figure S1)
We previously found that PGCCs could form spheroids in stem cell medium and acquired embryonic stemness marked by expression of OCT4, NANOG, and SOX2, which are involved in ovarian cancer relapse
Summary
Most deaths from ovarian cancer occur as a result of treatment resistance and relapse following chemotherapy [1,2,3]. We previously found that PGCCs could form spheroids in stem cell medium and acquired embryonic stemness marked by expression of OCT4, NANOG, and SOX2, which are involved in ovarian cancer relapse.
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