TMIC-10. AN IL-1{beta}/IL-1R PRO-TUMORIGENIC SIGNALING LOOP IN GLIOBLASTOMA

Glioblastoma (GBM) is the most aggressive and lethal malignant primary brain tumor in adults, with a high degree of intratumoral heterogeneity at both the cellular and molecular levels. The Cancer Genome Atlas (TCGA) project divided GBM into the proneural (PN), neural, classical, and mesenchymal (MES) subtypes based on distinct gene expression patterns. A further layer of complexity in GBM emerges from the tumor microenvironment in which these tumor cells develop and grow. The GBM microenvironment is composed of a wide variety of non-neoplastic stromal cells, including the vasculature, various infiltrating and resident immune cells, and other glial cell types. The most abundant non-neoplastic cell population in the GBM microenvironment is tumor-associated macrophages (TAMs). Of all the subtypes, PN-GBM is the most resistant to anti-neoplastic cell-specific targeted therapies, and high expression of TAM-related genes correlates with worse survival in PN patients only. In contrast, the MES-GBM subtype expresses the highest levels of TAM-enriched genes, and these tumors harbor higher numbers of TAMs compared to PN-GBM. To examine TAM-GBM interactions, we used a genetically-engineered mouse model of PN-GBM, and showed that tumor cells induce the expression of the key pro-inflammatory cytokine IL-1β in TAMs. This TAM-derived IL-1β activates IL-1β/IL-1R1 signaling in PN-GBM tumor cells, leading to increased stemness and growth, as well as increased expression of...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research