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

Evelyn Fessler,Jan Paul Medema,Tijana Borovski

doi:10.1186/s12943-015-0420-3

Abstract

BackgroundGlioblastoma 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.MethodsWe 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.ResultsConditioned 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0420-3) contains supplementary material, which is available to authorized users.

Highlights

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
Results tumor microvascular endothelial cells (tMVECs) increase self-renewal capacity and CD133 expression of CD133− GBM cells Populations expressing high levels of CD133 were shown to be enriched for CSCs in a wide variety of malignancies, including GBM [17, 18]
It is questionable whether CD133 identifies the CSC population in all GBM tumors, [19,20,21,22] its usefulness to identify cells that possess the capacity to self-renew, to spawn all differentiated progeny, and to serially propagate tumors has been well-documented in several primary spheroid cultured GBM lines [17, 18]

Summary

Introduction

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. Two recent studies showed that non-stem glioblastoma cells can convert to CSC-like cells upon therapeutic stress, such as TMZ treatment or Fessler et al Molecular Cancer (2015) 14:157 ionizing radiation [13, 14]. These results demonstrate that stochastic transition between distinct differentiation states - as has been described before for breast cancer - occurs in GBM [8, 13, 15, 16]. This approach does not exclude the existence of concealed CSCs not expressing the classical CSC markers which could expand upon treatment

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