Abstract 366: Downregulation of THBS1 is a critical step in glioblastoma angiogenesis.

Abstract

Abstract One of the hallmarks of Glioblastoma multiforme (GBM) is its abundant vasculature. These blood vessels support the tumor in a number of ways, including providing a niche for glioblastoma cancer stem cells. GBM tumors drive the formation of their vasculature and associated germinal niches through reciprocal inductive interactions between GBM cells and endothelial cells. Targeting the primary drivers of angiogenesis, VEGF and bFGF, in anti-angiogenic cancer treatments has value but is not curative. We hypothesize that identification of additional angiogenic molecules and pathways will provide new avenues for treatment. We used microarrays to perform global gene expression profiling to identify genes that are increased or decreased in expression as a consequence of functional interactions between GBM and brain microvascular endothelial cells. We identified several regulators of angiogenesis whose expression is modulated by this cell-cell interaction, but were particularly interested in the downregulation of Thrombospondin-1 (THBS1) and its associated receptors. THBS1 is a powerful anti-angiogenic protein and has previously been implicated in cancer, but its precise mechanism in glioblastoma angiogenesis is not yet known. A number of in-vitro experiments validated the importance of THBS1 in the interaction between GBM and endothelial cells. In-vivo mouse xenograft experiments showed that overexpression of THBS1 strongly inhibited tumor formation. We believe these results reveal the importance of factors other than VEGF in glioblastoma angiogenesis and provide a rationale to evaluate combinatorial targeted anti-angiogenic therapy for GBM. Citation Format: Michael D. Brooks, Erin Jackson, David Piwnica-Worms, Robi D. Mitra, Joshua B. Rubin. Downregulation of THBS1 is a critical step in glioblastoma angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2013-366