Transdifferentiation of glioblastoma cells into vascular endothelial cells

Yasushi Soda, Tomotoshi Marumoto, Dinorah Friedmann-Morvinski, Mie Soda, Fei Liu, Hiroyuki Michiue, Sandra Pastorino, Meng Yang, Robert M. Hoffman, Santosh Kesari, Inder M. Verma

    Research output: Contribution to journalArticlepeer-review

    363 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)4274-4280
    Number of pages7
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Issue number11
    DOIs
    Publication statusPublished - Mar 15 2011

    Keywords

    • Angiogenesis
    • Glioma
    • Hypoxia-inducible factor 1
    • Mouse model

    ASJC Scopus subject areas

    • General

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