Transdifferentiation of glioblastoma cells into vascular endothelial cells

DOI Web Site 被引用文献13件
  • Yasushi Soda
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;
  • Tomotoshi Marumoto
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;
  • Dinorah Friedmann-Morvinski
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;
  • Mie Soda
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;
  • Fei Liu
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;
  • Hiroyuki Michiue
    Department of Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan;
  • Sandra Pastorino
    Department of Neurosciences, Moore's Cancer Center, University of California at San Diego, La Jolla, CA 92093;
  • Meng Yang
    AntiCancer, Inc., San Diego, CA 92111; and
  • Robert M. Hoffman
    AntiCancer, Inc., San Diego, CA 92111; and
  • Santosh Kesari
    Department of Neurosciences, Moore's Cancer Center, University of California at San Diego, La Jolla, CA 92093;
  • Inder M. Verma
    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037;

説明

<jats:p> 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 <jats:sup>+/−</jats:sup> 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 <jats:sup>+</jats:sup> 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. </jats:p>

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