Stmc-31. stimulation of microglia and macrophages and growth attenuation of brain tumor-initiating cells with tumor necrosis factor-alpha

Microglia and macrophages (M/Ms) are functionally plastic entities that are compelled by glioblastoma (GBM) to adopt anti-inflammatory phenotypes and become major players in GBM progression. Understanding how to reverse this compulsion and maintain a pro-inflammatory tumor microenvironment is critical to developing effective therapeutics for GBM. Our studies have uncovered that GBM-associated M/Ms (GAM/Ms) can be pharmacologically compelled to shed the influence of GBM and secrete inhibitory factors that decrease the proliferation of GBM stem cell (GSC) lines and xenografts (Nature Neurosci 17:46-55, 2014). GSCs are a cellular reservoir that support GBM treatment resistance so it is important to development therapeutics that target this population. Our recent studies show that the most potent M/M-secreted factor behind GSC inhibition is tumor necrosis factor-alpha (TNF). We found that TNF decreases GSC proliferation and self-renewal through cytotoxic effects as well as G1 cell cycle arrest. TNF also induces differentiation in molecularly diverse GSCs. Additionally, we found that TNF can compel freshly-isolated human GAM/Ms to adopt a pro-inflammatory phenotype and inhibit GSCs in co-culture. The TNF receptors, TNFR1/2, are differentially expressed on GSCs and M/Ms. TNFR1, associated with apoptosis, is expressed by GSCs, while TNFR2, associated with survival mechanisms, is expressed on GAM/Ms. Moreover, TNFR1 on GSCs co-labels with OLIG2, one of the most specific markers of st...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research