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.
Glioblastoma is the most common and aggressive primary brain tumor and is universally fatal. Tumors are characterized by large, irregular blood vessels that promote tumor growth. We propose to reduce formation of these blood vessels in a novel fashion by targeting an inflammatory signaling pathway, thereby reducing tumor progression.
