• Impact of Myeloid Cell NF-κB Signaling on Glioblastoma Growth

      Venugopal, Natasha; Howard, Shelby; Achyut, Bhagelu; Jain, Meenu; Arbab, Ali; Bradford, Jennifer W.; Department of Biological Sciences (2017-03)
      Cancer consists of malignant tumor cells as well as supporting, non-cancerous cells that make up the tumor stroma. Tumor-associated macrophages (TAMs), a critical component of the stroma, can be present in very large numbers in a variety of cancers, and can lead to tumor progression through promotion of tumor inflammation, angiogenesis, invasion, and metastasis. Canonical nuclear factor-kappaB (NF-κB) pathway activity is very important in normal immune function, synaptic plasticity, and memory, and aberrant NF-κB activity is associated with autoimmune disease, and importantly, cancer. Previous studies have been reported about the importance of tumor cell associated NF-κB signaling in cancers. As myeloid cell NF-κB signaling may also be important in promoting cancers, we have been utilizing the p65fl/fl/LysMCre transgenic animal model, which lacks p65 protein in cells of the myeloid lineage, to study the impact of myeloid cell derived NF-κB signaling in glioblastoma (GBM), an extremely aggressive brain cancer. This transgenic model has a very efficient deletion of p65 protein and drastically reduced NF-κB signaling in bone marrow derived macrophages (BMDMs), but brain residing microglia do not have significantly lower p65 levels as compared to control microglia. Even with this finding, p65fl/fl/LysMCre mice implanted with syngeneic GBM cells have significantly reduced GBM tumor burden than LysMCre control mice, as measured by magnetic resonance imaging. This result underscores the potential importance of bone marrow cells that migrate to the tumor site and significantly contribute to GBM growth. This work also indicates the potential benefits of targeting myeloid specific NF-κB signaling in GBM patients.