Transdifferentiation of glioblastoma cells into vascular endothelial cells

Abstract

Glioblastoma (GBM) is the most malignant brain tumor and is highly resistant to intensive combination therapies and anti-VEGF therapies. To assess the resistance mechanism to anti-VEGF therapy, we examined the vessels of GBMs in tumors that were induced by the transduction of p53 +/− heterozygous mice with lentiviral vectors containing oncogenes and the marker GFP in the hippocampus of GFAP-Cre recombinase (Cre) mice. We were surprised to observe GFP + vascular endothelial cells (ECs). Transplantation of mouse GBM cells revealed that the tumor-derived endothelial cells (TDECs) originated from tumor-initiating cells and did not result from cell fusion of ECs and tumor cells. An in vitro differentiation assay suggested that hypoxia is an important factor in the differentiation of tumor cells to ECs and is independent of VEGF. TDEC formation was not only resistant to an anti-VEGF receptor inhibitor in mouse GBMs but it led to an increase in their frequency. A xenograft model of human GBM spheres from clinical specimens and direct clinical samples from patients with GBM also showed the presence of TDECs. We suggest that the TDEC is an important player in the resistance to anti-VEGF therapy, and hence a potential target for GBM therapy.

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

“…smooth muscle cells, pericytes). 16,[25][26][27][28][29] One possible explanation for this discrepancy is that the lineage specification may be linked to the GBM/GSC subtypes. Given that neural stem cells are known to transdifferentiate into endothelial cells, 30 the proneural GSC subtype may have the potential to give rise to endothelial cells rather than stromal cells.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…For instance, some tumors can grow along pre‐existing blood vessels without evoking an angiogenic response (and indeed are refractory to VEGF blockade); this process is referred to as vascular co‐option (Carmeliet and Jain, 2011a) and is specially observed in well‐vascularized tissues such as the brain (Holash et al., 1999). Other tumors may display vasculogenic mimicry, a process by which tumor cells alter their gene expression profile toward an undifferentiated phenotype, and gain the ability to form vascular‐like structures that do not depend on VEGF for their growth (Maniotis et al., 1999; Soda et al., 2011). If such vascular subtleties are not recapitulated in transplant tumor models representing a particular organ‐specific cancer, then targeted antiangiogenic drugs may fail to accurately demonstrate their effects and limitations.…”

Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies

“…9 An additional means by which angiogenesis occurs in glioblastoma is through so-called vascular mimicry. [10][11][12][13] Separate from blood vessels produced through the angiogenic signaling described above, glioma stem-like cells have been shown to differentiate into vascular endothelial cells both in culture and in xenografts. These non-VEGF-dependent endothelial cells hold genetic markers similar to the surrounding glioma tissue, such as amplification of epidermal growth factor receptor or mutation of TP53.…”