Transdifferentiation of glioblastoma cells into vascular endothelial cells
Yasushi Soda1, Tomotoshi Marumoto, Dinorah Friedmann-Morvinski
1Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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.
Insights
Tumor-derived endothelial cells (TDECs) originate from glioblastoma cells, contributing to resistance against anti-VEGF therapy. Targeting TDECs may offer a new therapeutic strategy for glioblastoma treatment.
Area of Science:
- Neuro-oncology
- Cancer biology
- Vascular biology
Background:
- Glioblastoma (GBM) exhibits high resistance to current therapies, including anti-VEGF treatments.
- The precise mechanisms underlying GBM's resistance to anti-VEGF therapy require further elucidation.
Purpose of the Study:
- To investigate the origin of vascular endothelial cells (ECs) in GBM.
- To understand the role of tumor-derived endothelial cells (TDECs) in anti-VEGF therapy resistance.
Main Methods:
- Induction of GBM in p53(+/-) heterozygous mice using lentiviral vectors and GFAP-Cre recombinase.
- Transplantation of mouse GBM cells and in vitro differentiation assays.
- Xenograft models using human GBM spheres and analysis of clinical GBM samples.
Main Results:
- Observed GFP(+) vascular endothelial cells (ECs) in induced GBM, identified as tumor-derived endothelial cells (TDECs).
- Demonstrated that TDECs originate from tumor-initiating cells, not cell fusion.
- Hypoxia identified as a key factor in TDEC differentiation, independent of VEGF.
- TDEC formation showed resistance to anti-VEGF receptor inhibitors and increased in frequency.
Conclusions:
- TDECs are a significant factor in glioblastoma's resistance to anti-VEGF therapy.
- TDECs represent a potential therapeutic target for overcoming GBM treatment resistance.
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