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Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme

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Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs, such as bevacizumab (Avastin), an anti-VEGF antibody. However, these clinical studies have shown that most patients become resistant to anti-VEGF therapy after an initial response. Recent studies have revealed some resistance mechanisms against anti-VEGF therapies involved in several types of cancer. In this review, we address mechanisms of angiogenesis, including unique features in GBMs, and resistance to anti-VEGF therapies frequently observed in GBM. Enhanced invasiveness is one such resistance mechanism and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.

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Acknowledgments

We thank B. Coyne for administrative assistance. IMV holds the Irwin and Joan Jacobs Chair in Exemplary Life Science. This work was supported in part by grants from the NIH (HL053670), NCI Cancer Center Core Grant (P30 CA014195-38), NCI Training Grant T32CA009370 (AR), the American Brain Tumor Association (CM), and the H.N. and Frances C. Berger Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Award recipients are required to comply with the NIH Public Access Policy.

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  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Yasushi Soda, Chad Myskiw, Amy Rommel & Inder M. Verma

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  1. Yasushi Soda
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  2. Chad Myskiw
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  3. Amy Rommel
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  4. Inder M. Verma
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Correspondence to Inder M. Verma.

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Yasushi Soda, Chad Myskiw, and Amy Rommel contributed equally to this manuscript.

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Soda, Y., Myskiw, C., Rommel, A. et al. Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme. J Mol Med 91, 439–448 (2013). https://doi.org/10.1007/s00109-013-1019-z

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  • DOI: https://doi.org/10.1007/s00109-013-1019-z

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