Abstract 4864: Tumor promoting role of NF-kappa B in the glioma environment

Abstract

Abstract Introduction: Gliomas are the most common primary malignant brain tumors. Their characteristic features are extensive growth and lack of the clear borders due to diffuse invasion of surrounding tissue. Invasive glioma cells have been shown to interact through soluble signals with other cells in the neural microenvironment, which is normally highly inhibitory to cell motility. This communication changes the behavior of the tumor microenvironment to become permissive and facilitate tumor invasion. Here, we investigated the role of NFκB signaling in the glioma microenvironment and demonstrate that activation of NFκB in neural cells is critical for tumor growth and invasion. Methodology: We analyzed the growth and invasion of malignant gliomas using an NFκB-deficient mouse model (RelA(p65)-/- TNFR1-/-). Since p65-/- mice do not survive to adulthood, mouse glioma cells were implanted in p65+/- mice (which have significantly reduced NFκB activity) or their control littermates. Organotypic cultures of p65-/- brain slices and cultures of p65-/- neonatal astrocytes were used to assess the role of active NFκB signaling in astroglia on tumor invasion. Results: Using the mouse glioma cell line GL261 (poorly invasive) we observed significantly reduced tumor volume in NFκB -deficient mice compared to wild-type littermates. Further studies using mouse glioma stem-like cells Mut4 (highly invasive; GFAP-Cre: Nf1loxP/+ Trp53-/+ PTENloxP/+; Alcantara-Llaguno et al., Cancer Cell, 2009) demonstrated reduction both in tumor size and extent of invasion in the NFκB-deficient microenvironment. Importantly, immunohistochemical analysis demonstrated significantly reduced number of protoplasmic GFAP- positive astrocytes surrounding the tumors in p65+/- brains. Further analysis in brain slice cultures showed that invasion of glioblastoma cells was highly reduced through p65+/- tissue. Moreover, p65+/- astrocytes exhibited significantly reduced responses towards glioma cells, including reduced invasion through Matrigel in response to signals released by GL261 cells. Conclusions: Our results strongly suggest that NFκB signaling may be involved in the recruitment or activation of reactive astrocytes surrounding the invasive borders of gliomas. This activation is likely necessary for enhanced tumor invasion through brain tissue. Our results highlight the relevance of the astroglial compartment as a collateral target that should be considered in future strategies targeting brain tumor invasion. Citation Format: Aneta Kwiatkowska, Mohan Sobana Nandhu, Mariano Sebastian Viapiano. Tumor promoting role of NF-kappa B in the glioma environment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4864. doi:10.1158/1538-7445.AM2014-4864