Functions of NF-κB in the Tumor Microenvironment

Abstract

NF-κB is a master transcription factor whose signaling pathway regulates the expression of genes involved in a substantial number of pathways including immunity, cell survival, cell death, inflammation, and proliferation. NF-κB has been shown to promote and suppress tumor development, however, the molecular mechanism underlying this contrasting role of NF-κB is unknown. Our central hypothesis is that the relative functions of NF-κB in immune cells and tumor cells control the dynamic interactions between immune and tumor cells in the tumor microenvironment to dictate tumor progression or regression. To test this hypothesis, we studied NF-κB expression and function in myeloid cells, T cells, and tumor cells. Here we provide evidence for the specific roles of NF-κB in 1) iNOS expression in myeloid and tumor cells and 2) radiation-induced TNFα and Fas expression in tumor cells. In the first publication, we found that iNOS is expressed in colon carcinoma cells and tumor-infiltrating immune cells. We not only show that NF-κB is specifically binding to the nos2 promoter in both human colon carcinoma cells and murine myeloid cells, but specifically a p65/p65 and p50/p50 homodimer is binding to the nos2 promoter in myeloid cells. In the second publication, we found that radiation induces rapid activation of NF-κB in human soft tissue sarcoma. Specifically, radiation is activating the p65/p50 heterodimer and p50/p50 homodimer that is then binding to TNFα and FAS promoter sequences. Using a syngeneic mouse model, irradiated tumors had a significant reduction in tumor growth and induced a Th1/Tc1 T cell response, shown by an increase in signature genes of T cells in which NF-κB has been reported to be a transcriptional activator. NF-κB therefore acts as a molecular link between tumor cells and immune cells in the tumor microenvironment in irradiated tumors. In summary, our data indicate that the different NF-κB dimers regulate the expression of both tumor suppressors such as Fas and tumor promoters such as iNOS. Therefore, the cellular context-dependent NF-κB dimer composition might underlie the contrasting NF-κB functions in tumor promotion or suppression through regulating the expression of genes with opposite functions during tumor development.