No abstract

Recent evidence has shown that glioblastoma stem-like cells (GSCs) can transdifferentiate into endothelial cells and vascular-like tumor cells. The latter pattern of vascularization indicates an alternative microvascular circulation known as vasculogenic mimicry (VM). However, it remains to be clarified how the GSC-driven VM makes a significant contribution to tumor vasculature. Here, we investigated eleven cases of glioblastomas and found that most of them consisted of blood-perfused vascular channels that co-express mural cell markers smooth muscle alpha actin and platelet-derived growth factor receptor β, epidermal growth factor receptor, and vascular endothelial growth factor receptor 2 (Flk-1), but not CD31 or VE-cadherin. This microvasculature co-existed with endothelial cell-associated vessels. GSCs derived from patients with glioblastomas developed vigorous mural cell-associated vascular channels but few endothelial cell vessels in orthotopic animal models. Suppression of Flk-1 activity and gene expression abrogated GSC transdifferentiation and vascularization in vitro, and inhibited VM in animal models. This study establishes mural-like tumor cells differentiated from GSCs as a significant contributor to microvasculature of glioblastoma and points to Flk-1 as a potential target for therapeutic intervention which could complement current anti-angiogenic treatment.

Background:The malignancy of glioblastoma is characterized by strong vascularization, including vasculogenic mimicry and angiogenesis. Results: Glioblastoma cells promote vasculogenic mimicry and tumor development via Flk-1 activation. Conclusion: Glioblastoma cells display the ability to constitute vascular channels. Significance: Identification of Flk-1 as a key factor regulating vasculogenic mimicry could offer a novel therapeutic target for patient treatment.