title: Inflammatory landscape of human brain tumors reveals an NFκB dependent cytokine pathway associated with mesenchymal glioblastoma.
abstract: 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 as IL6, IL8 and CCL2 are 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.
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas (CCB), Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: alfeu.zanotto@ufsc.br.
authors.forename: Alfeu
authors.initials: A
authors.lastname: Zanotto-Filho
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Rosângela Mayer
authors.initials: RM
authors.lastname: Gonçalves
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Karina
authors.initials: K
authors.lastname: Klafke
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Priscila Oliveira
authors.initials: PO
authors.lastname: de Souza
authors.affiliation: Instituto de Informática, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Fabiane Cristine
authors.initials: FC
authors.lastname: Dillenburg
authors.affiliation: Instituto de Informática, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Luigi
authors.initials: L
authors.lastname: Carro
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Daniel Pens
authors.initials: DP
authors.lastname: Gelain
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: José Cláudio Fonseca
authors.initials: JC
authors.lastname: Moreira
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D008648:Mesoderm / Q000503:physiopathology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D016328:NF-kappa B
keywords: Disease subtypes; Glioma; Inflammation; NFκB