Mural Cell Transdifferentiation Of Glioblastoma Stem-Like Cells Drives Vasculogenic Mimicry In Glioblastoma Development

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Glioblastomas (GBM) are extremely aggressive and have the poorest prognosis among brain tumors. These tumors display extensive microvasculature that presumably originates from endothelial cell angiogenesis. Indeed, many anti-angiogenic therapies have been accepted for glioblastoma treatment based on this premise. Recent evidence has shown that glioblastoma stem-like cells (GSCs) can differentiate into endothelial cells that participate in angiogenesis (Ricci-Vitiani L et al., Nature 2010;468:824-29, Wang et al., Nature 2010;468:829-33, & Soda et al., PNAS 2011; 108:4274-80). However, it remains to be clarified if these GSC-derived endothelial cells make a significant contribution to tumor vasculature. Here, we surveyed eleven GBM cases and found that glioblastomas consisted of 34.1% of endothelial cell-associated vasculature, while 59.7% of microvasculature arose from mural-like tumor cells that co-express mural cell markers smooth muscle alpha actin and platelet-derived growth factor receptor, and VEGF receptor 2 (Flk-1), but not CD31, CD34 or VE-cadherin. This pattern of vascularization indicates an alternative microvascular circulation known as vasculogenic mimicry (VM). GSCs derived from patients with GBM displayed the multipotency of neuronal stem cells capable of transdifferentiation into mural-like tumor cells that promoted VM. GSCs developed vigorous mural cell-associated vascular channels but few endothelial cell vessels in orthotopic brain tumor models. Furthermore, the development of these tumor cell-associated channels was dependent on expression of VEGF receptor 2 (Flk-1). Suppression of Flk-1 activity and gene expression by a variety of different inhibitory approaches abrogated GSC transdifferentiation and vascularization in vitro, and inhibited VM in xenografted tumor models in vivo. Collectively, this study establishes a pivotal role for transdifferentiation of GSCs in the development of VM, which contributes to an aggressive phenotype of GBM, and points to Flk-1 as a potential target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1024. doi:1538-7445.AM2012-1024