The Role of IL-1 in Glioblastoma-Associated Angiogenesis and Tumor Progression

Emory University, Atlanta GA

Investigators

Linked publications, trials & patents

Abstract

Description: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The histological hallmarks of GBM are pseudopalisading necrosis and microvascular proliferation. Both hallmarks result from tumor-driven angiogenesis, driving the formation of irregular, dysfunctional blood vessels. Our preliminary data indicates that PDGFB-driven murine GBM displays tortuous, leaky blood vessels. Moreover, these tumors contain high levels of tumor-associated macrophages (TAMs), cells that are known to be involved in angiogenesis and metastasis. We also demonstrate that TAMs upregulate and produce high levels of the IL-1 family of cytokines as well as the pro-angiogenic factors VEGFA and various MMPs. Literature suggests that the IL-1 family of cytokines are implicated in cancer-related angiogenesis as well as tumor growth. This has not been investigated in the context of GBM, however. Therefore, this project aims to dissect the role that IL-1 signaling plays in angiogenesis in PDGFB-driven tumors. In vitro experiments will uncover the gene expression changes in primary murine macrophages following stimulation with the IL-1 cytokines IL-1? and IL-1?, with a focus on VEGFA and MMPs. This analysis will be performed utilizing RNA-sequencing, qRT-PCR, and ELISA. Moreover, these experiments will investigate the effects of IL-1 stimulation on the growth of glioma stem cells using flow cytometry-based cell cycle analysis. In vivo experiments will use the RCAS/tv-a system to generate PDGFB-driven murine GBM. Genetic ablation of both the ligands IL-1? and IL-1? as well as the receptor IL- 1R1 will determine the role of these IL-1 cytokines in PDGFB-driven GBM angiogenesis and growth. Pharmacological blockade of the IL-1R1 will assess inhibition of IL-1 signaling as a novel therapy for GBM. The in vivo experiments will utilize immunohistochemistry, a functional blood vessel integrity assay, MRI, RNA- sequencing, qRT-PCR, and flow cytometry. These experiments will solidify the role of IL-1? and IL-1? signaling in angiogenesis related to PDGFB-driven GBM and lay the groundwork for inhibition of IL-1 signaling as a novel therapy for GBM.