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 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.

Brain mesenchymal stem cells: The other stem cells of the brain?

“…Importantly, glioblastoma stem cells are able to transdifferentiate into pericytes [80] . According to the function of pericytes in vessel formation, these cancer pericytes contribute to the glioblastoma microvasculature [80,81] . The recent finding that MSCs are pericytes, and that glioblastoma cells generate cancer pericytes, suggests that the stemness potential of pericytes could play a yet unsuspected role in cancer formation and progression.…”

“…Cancer stem cells are then recruited to develop vessels by endothelial cell-secreted cytokines such as CXCL12 [83][84][85] (Figure 3, step 3). In this novel vascular microenvironment made of chaotic vessels, cancer stem cells reacquire a pericyte-like phenotype as described [80,81] . These pericyte-like cancer cells not only participate to tumor vascularization [80,81] , but also re-express their mesenchymal potential by undergoing a mesenchymal transition reminiscent to the epithelial mesenchymal transition.…”

“…In this novel vascular microenvironment made of chaotic vessels, cancer stem cells reacquire a pericyte-like phenotype as described [80,81] . These pericyte-like cancer cells not only participate to tumor vascularization [80,81] , but also re-express their mesenchymal potential by undergoing a mesenchymal transition reminiscent to the epithelial mesenchymal transition. This generates the perpetuum mobile described in Figure 3.…”

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

“…In desmoplastic areas of treated tumors, we often observed cytoplasmic CD31 expression in nonendothelial cells. This phenomenon has been documented before and has been linked to the phenomenon of vasculogenic mimicry (27,28). Third, the current trial was not designed to assess the duration of the sorafenibinduced decreased antibody uptake.…”

Individual roles of p53 and NF1 in OPC Competition and Gliomagenesis

“…However, one caveat of these studies is that they analyzed tumors at the end stage, when tumor cells have acquired multiple changes which could result in their altered expression patterns and trans differentiation which has been previously reported (Scully et al, 2012;Soda et al, 2011).…”