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-kB) signaling pathway is a key mediator of tumorigenesis by linking inflammatory pathways to cancer. Inhibitors of NF-kB potentiate the effects of cytotoxic agents in ovarian cancer cells. Thus, a promising strategy in ovarian cancer treatment is the combination of NF-kB inhibitors with current platinum- based regimens. Equally relevant are the potential effects of NF-kB inhibition in host cells such as peritoneal macrophages, thought to play a pro-tumor role during ovarian cancer progression. We will define patterns of NF-kB activity in host cells using NF-kB reporter (NGL) transgenic mice injected with mouse ID8 ovarian cancer cells. NF-kB activity in tumor cells will be monitored through stable transfection of the NGL reporter. We have begun to characterize these syngeneic models to determine reliable end-points measuring tumor burden and to establish markers of macrophage function. We have detected substantially increased NF-kB reporter activity in tumor cells in late stages of progression. Finally, we have shown that the NF-kB inhibitor Thymoquinone (TQ) induces antitumor effects in ovarian cancer cells alone and in combination with cisplatin, but induces an unexpected promotion of progression in vivo.