Inflammatory landscape of human brain tumors reveals an NF[kappa]B dependent cytokine pathway associated with mesenchymal glioblastoma

• Published in: Cancer letters Vol. 390; p. 176
• Main Authors: Zanotto-Filho, Alfeu, Gonçalves, Rosângela Mayer, Klafke, Karina, de Souza, Priscila Oliveira, Dillenburg, Fabiane Cristine, Carro, Luigi, Gelain, Daniel Pens, Moreira, José Cláudio Fonseca
• Format: Journal Article
• Language: English
• Published: Clare Elsevier Limited 01.04.2017
• Subjects: Angiogenesis; Brain cancer; Cancer; Cancer therapies; Cytokines; Gene expression; Kinases; Studies; Tumor necrosis factor-TNF; Tumors
• DOI: 10.1016/j.canlet.2016.12.015
• ISSN: 0304-3835

The tumor microenvironment is being increasingly recognized as a key factor in cancer aggressiveness. In this study, we characterized the inflammatory gene signatures altered in glioma cell lines and tumor specimens of differing histological and molecular subtypes. The results showed that glioblastoma multiforme (GBM) shows upregulation of a subset of inflammatory genes when compared to astrocytomas and oligodendrogliomas. With molecular subtypes of GBM, the expression of inflammatory genes is heterogeneous, being enriched in mesenchymal and downregulated in Proneural/GCIMP. Other inflammation-associated processes such as tumor-associated macrophage (TAM) signatures are upregulated in mesenchymal, and a subset of 33 mesenchymal-enriched inflammatory and TAM markers showed correlation with poor survival. We found that various GBM tumor-upregulated genes such asIL6, IL8andCCL2are also actively expressed in glioma cell lines, playing differential and cooperative roles in promoting proliferation, invasion, angiogenesis and macrophage polarization in vitro. These genes can be stimulated by pathways typically altered in GBM, including the EGFR, PDGFR, MEK1/2-ERK1/2, PI3K/Akt and NFκB cascades. Taken together, the results presented herein depict some inflammatory pathways altered in gliomas and highlight potentially relevant targets to therapy improvement.