Endothelial cells induce cancer stem cell features in differentiated glioblastoma cells via bFGF

Abstract

Background: Glioblastoma multiforme (GBM) is a rapidly growing malignant brain tumor, which has been reported to be organized in a hierarchical fashion with cancer stem cells (CSCs) at the apex. Recent studies demonstrate that this hierarchy does not follow a one-way route but can be reverted with more differentiated cells giving rise to cells possessing CSC features. We investigated the role of tumor microvascular endothelial cells (tMVECs) in reverting differentiated glioblastoma cells to CSC-like cells. Methods: We made use of primary GBM lines and tMVECs. To ensure differentiation, CSC-enriched cultures were forced into differentiation using several stimuli and cultures consisting solely of differentiated cells were obtained by sorting on the oligodendrocyte marker O4. Reversion to the CSC state was assessed phenotypically by CSC marker expression and functionally by evaluating clonogenic and multilineage differentiation potential. Results: Conditioned medium of tMVECs was able to replenish the CSC pool by phenotypically and functionally reverting differentiated GBM cells to the CSC state. Basic fibroblast growth factor (bFGF), secreted by tMVECs, recapitulated the effects of the conditioned medium in inducing re-expression of CSC markers and increasing neurosphere formation ability of differentiated GBM cells. Conclusions: Our findings demonstrate that the CSC-based hierarchy displays a high level of plasticity showing that differentiated GBM cells can acquire CSC features when placed in the right environment. These results point to the need to intersect the elaborate network of tMVECs and GBM CSCs for efficient elimination of GBM CSCs.