Epithelial to endothelial transition in glioblastoma: Angiogenesis

Glioblastoma multiforme (GBM) is highly incurable and one of the most aggressive and invasive primary brain tumors in adults, with abnormal vascularization. Tumor vascularization was considered as sprouting of new blood vessels from pre-existing ones composed of non-malignant endothelial cells into tumor mass. However, vasculogenic mimicry (VM) is defined as the generation of vascular channels via aggressive tumor cells in the tumor, probable responsible in the failure of anti-angiogenic therapies. Both VM and transdifferentiation of cancer stem cells into endothelial cells were reported in GBM. However, molecular mechanisms underlying the vasculogenesis of glioblastoma have not been fully identified yet. Epithelial-mesenchymal transition (EMT) is a dynamic, reversible process, playing causal role in the enhancement of metastatic potential of tumor cells. EMT may play role in angiogenesis and vasculogenic mimicry. Mitochondrial DNA (mtDNA) depletion is an important contributor to cancer malignancy. Although mtDNA depletion occurs in gliomas, the association between mtDNA depletion and EMT, their role in glioblastoma vasculogenesis is unknown. In this study, it was asked whether mtDNA depletion causes the acquisition of EMT phenotype and a subsequent increase in vasculogenic properties and differentiation potential into endothelial lineage in glioblastoma cells. U87-MG and A172 cell lines were used as GBM models. mtDNA was depleted using ethidium bromide (EtBr). mtDNA depletion induced EMT through upregulation of mesenchymal marker expression. Consistent with increased EMT properties, tubular network formation on Matrigel, invasion through a transwell system, spheroid formation and endothelial differentiation capacity were increased in mtDNA depleted cells compared to those in parental cells. Low mtDNA content induces EMT, increased VM properties and endothelial differentiation capacity together with invasiveness. In this study, mitochondrial stress was found as a crucial contributor for the acquisition of EMT and increase in vasculogenic properties in GBM, which may be a therapeutic target for glioblastoma treatment.