Transdifferentiation of glioblastoma cells into vascular endothelial cells.
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.
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Yasushi
Y
Soda
Tomotoshi
T
Marumoto
Dinorah
D
Friedmann-Morvinski
Mie
M
Soda
Fei
F
Liu
Hiroyuki
H
Michiue
Sandra
S
Pastorino
Meng
M
Yang
Robert M
RM
Hoffman
Santosh
S
Kesari
Inder M
IM
Verma
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002459:Cell Fusion; D015687:Cell Hypoxia; D054338:Cell Transdifferentiation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor
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