IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming

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.

Stress-Induced Polyploid Giant Cancer Cells: Unique Way of Formation and Non-Negligible Characteristics

Polyploidy is a conserved mechanism in cell development and stress responses. Multiple stresses of treatment, including radiation and chemotherapy drugs, can induce the polyploidization of tumor cells. Through endoreplication or cell fusion, diploid tumor cells convert into giant tumor cells with single large nuclei or multiple small nucleuses. Some of the stress-induced colossal cells, which were previously thought to be senescent and have no ability to proliferate, can escape the fate of death by a special way. They can remain alive at least before producing progeny cells through asymmetric cell division, a depolyploidization way named neosis. Those large and danger cells are recognized as polyploid giant cancer cells (PGCCs). Such cells are under suspicion of being highly related to tumor recurrence and metastasis after treatment and can bring new targets for cancer therapy. However, differences in formation mechanisms between PGCCs and well-accepted polyploid cancer cells are largely unknown. In this review, the methods used in different studies to induce polyploid cells are summarized, and several mechanisms of polyploidization are demonstrated. Besides, we discuss some characteristics related to the poor prognosis caused by PGCCs in order to provide readers with a more comprehensive understanding of these huge cells.

Polyploid Giant Cancer cells and ovarian Cancer: New insights into mitotic regulators and polyploidy

Summary sentence: Cytotoxic drugs frequently used in ovarian cancer treatment impact tumor cell cycle progression and the emergence of polyploid cells where genetic and epigenetic events ultimately lead to drug resistant diploid progeny.

Polyploid giant cancer cells and their role in the formation of resistance to therapeutic treatment

The review considers the properties of polyploid giant tumor cells a new target for the development of cancer therapy. Various number of polyploid giant tumor cells are detected in almost all human solid tumors. Their number increases under the influence of hypoxia, radiation, and after chemotherapy. Previously, these cells were not considered to be worth studying as they do not proliferate and eventually die as a result of one of the cell death mechanisms action. Recent data have demonstrated that polyploid giant cells can give rise to daughter cells that possess tumorigenicity and are characterized as stem tumor cells. Giant tumor cells and daughter cells are involved in the processes of metastasis, recurrence, drug resistance formation and radio-resistance of tumors. The search is under way for molecular targets that could prevent the appearance or contribute to the elimination of previously formed polyploid giant tumor cells. The combination of traditional therapy that causes the death of proliferating tumor cells and allows their elimination, with the use of tools that could prevent the appearance of resistant polyploid giant cells and their daughter cells, can be the key to the effective treatment of malignancies.