Inhibition of NF-κB signaling ablates the invasive phenotype of glioblastoma

• Published in: Molecular cancer research 2013-12, Vol.11 (12), p.1611-1623
• Main Authors: Westhoff, Mike-Andrew, Zhou, Shaoxia, Nonnenmacher, Lisa, Karpel-Massler, Georg, Jennewein, Claudia, Schneider, Matthias, Halatsch, Marc-Eric, Carragher, Neil O, Baumann, Bernd, Krause, Alexander, Simmet, Thomas, Bachem, Max G, Wirtz, Christian R, Debatin, Klaus-Michael
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Movement - drug effects; Disulfiram - pharmacology; Enzyme Inhibitors - pharmacology; Fibronectins - metabolism; Gene Expression Regulation, Neoplastic; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Metalloproteases - genetics; Metalloproteases - metabolism; Mice; Neoplasm Invasiveness; NF-kappa B - genetics; NF-kappa B - metabolism; Signal Transduction - drug effects; Tumor Microenvironment
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-13-0435-T

Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here, it is demonstrated that the invasive phenotype of glioblastoma multiforme is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMP), regulates fibronectin processing. Both, cell lines and tumor stem cells from primary glioblastoma multiforme, secrete high levels of fibronectin which when cleaved by MMPs forms an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, glioblastoma multiforme cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane assay. Furthermore, having delineated the underlying molecular mechanism of glioblastoma multiforme invasion, the potential of a disulfiram-based therapy was revealed in a highly invasive orthotrophic glioblastoma multiforme mouse model. This study defines a novel therapeutic approach that inhibits micrometastases invasion and reverts lethal glioblastoma into a less aggressive disease.