Nuclear Factor-Kappa B Activity in the Host-Tumor Microenvironment of Ovarian Cancer.

摘要

Overcoming tumor resistance to platinum chemotherapy is critical for prolonging life in women with advanced ovarian cancer. The nuclear factor-kappaB (NF- B) signaling pathway is a key mediator of tumorigenesis by linking inflammatory pathways to cancer. Inhibitors of NF- B such as thymoquinone (TQ) potentiate the effects of cytotoxic agents, including cisplatin, in ovarian cancer cells. Equally relevant are the potential effects of NF- B inhibition in host cells such as peritoneal macrophages, thought to play pro-tumor (M2-like) or anti-tumor (M1-like) roles during ovarian cancer progression. We defined patterns of NF- B activity in (i) ID8 tumor cells stably expressing the NGL NF- B reporter plasmid, and (ii) in host cells in ID8-injected NGL reporter mice. We showed increased NF- B reporter activity in tumor cells and in host macrophages during progression, and increased markers of M2 macrophages in ascites fluid. Reducing NF- B activity in tumor cells with TQ treatment elevated expression of M1 macrophage markers, while longer-term TQ treatment lead to increased ascites, elevated NF- B signaling and elevated expression of M2 markers. Combined TQ and cisplatin treatment lead to synergistic anti-tumor effects in vitro, reduced tumor burden and apoptotic marks in tumors to a greater extent than treatment with cisplatin alone, reduced M2 and induced M1 macrophage markers, and decreased levels of known pro-tumorigenic cytokines in ascites fluid.