Abstract 265: c-Myc and NFκB are reciprocal and contextual transcriptional regulators of glioma cell proliferation or invasion

Abstract Classic histological features of glioblastoma include dense proliferative areas rich in angiogenesis as well as centripetal dissemination of neoplastic cells into adjacent brain tissue (most frequently white matter). The infiltrative dispersion patterns of malignant glioma preclude complete tumor resection; growth of satellite lesions causes significant neurological morbidity and mortality, and accounts for much of the post-treatment, recurrent (fatal) disease. Distinct transcriptomes are discernable between GBM cells at the tumor core and invasive rim, and many of the differentially-expressed genes are co-associated with migration and the collateral phenotype of cell survival; reciprocal downregulation of genes in invasive glioma cells are ontologically associated with proliferation. Our studies of glioma cells from paired core and rim human biopsy specimens reveal a higher proliferative index (Ki67 Mib-1 IHC score) at the core as compared to the rim (19 out of 35 specimens) p < 0.002. Analysis of activation states of transcription factors (Luminex multiplex assay) revealed that nuclear c-myc activity is up in the tumor core while nuclear NFκB activity is up at the invasive rim of the tumor. Depletion of c-myc (siRNA oligonucleotides) resulted in an increase in the migration rate of glioma cells in vitro, whereas inhibition of NFκB by SN50 resulted in a decrease in migration rate both in vitro and ex vivo (rat brain slice). Immunohistochemical validation using a glioma tissue microarray containing paired core and rim biopsy specimens showed that phosphorylated c-myc staining was higher in the core than in the rim for 23 out of 39 biopsy specimens scored, and that phosphorylated NFκB was higher in the rim than the core for 30 out of 43 biopsy specimens scored. The Go vs Grow hypothesis suggests cell proliferation and cell migration are temporally exclusive behaviors and tumor cells postpone cell division for migration. Our findings argue that differential suppression/activation of c-myc and NFκB underlie the shift of glioma cells from growing to going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 265. doi:10.1158/1538-7445.AM2011-265