title: Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas.
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 11 cases of glioblastomas and found that most of them consisted of blood-perfused vascular channels that coexpress mural cell markers smooth muscle α-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 coexisted 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 that could complement current anti-angiogenic treatment.
authors.affiliation: Pioneer Valley Life Sciences Institute, University of Massachusetts, Amherst, Springfield, Massachusetts 01107, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Scully
authors.forename: Ralph
authors.initials: R
authors.lastname: Francescone
authors.forename: Michael
authors.initials: M
authors.lastname: Faibish
authors.forename: Brooke
authors.initials: B
authors.lastname: Bentley
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Taylor
authors.forename: Dennis
authors.initials: D
authors.lastname: Oh
authors.forename: Robert
authors.initials: R
authors.lastname: Schapiro
authors.forename: Luis
authors.initials: L
authors.lastname: Moral
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Rong
authors.initials: R
authors.lastname: Shao
mesh_terms: D002454:Cell Differentiation; D042783:Endothelial Cells / Q000473:pathology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D014407:Tumor Cells, Cultured