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

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.

Figure 1. Tumor derived endothelial cells (TDECs)

Confocal microscope images of vascular endothelial cells (ECs) in mouse GBM. (A) Regular ECs line the vessel lumen and express EC marker Von Willebrand factor (vWF) but not tumor marker GFP. (B) In contrast, TDECs express both vWF and GFP. DAPI was used as a nuclear marker. (C) Expression of EC antigens CD31 (upper panels), CD34 (middle panels) and CD144 (lower panels) in TDECs. Some GFP⁺ ECs (arrows in upper right panel) form vessels with GFP⁻ regular ECs (arrowheads). DAPI was used as nuclear marker and the image was incorporated in the merge panels. All confocal pictures are single slice images at Airy factor of 1.0. Original magnification: x63 with 3x electrical zoom (189x total magnification). These images were reprinted from Ref. and reorganized.

Figure 2. Characterization of VEGFR2 in TDECs

Confocal microscope images of TDECs in mouse GBM. (A) Regular tumor ECs express VEGFR2 (upper panels) but (B) TDECs did not express VEGF-R2 (lower panels). DAPI was used as nuclear marker and the image was incorporated in the merge panels. All confocal pictures are single slice images at Airy factor of 1.0. Original magnification: x63 with 3x electrical zoom (189x total magnification). These images were reprinted from Ref. and reorganized.

Figure 3. Transdifferentiation of tumor initiating neuro-progenitor cells into endothelial cells

Upon oncogenic insult, such as loss of NF1 and p53, terminally differentiated glia or neurons can de-differentiate into tumor initiating neuro-progenitor cells. These cells can self-renew and also differentiate into astrocytes, neurons and oligodendrocytes. Tumor initiating neuro-progenitor cells can also transdifferentiate into endothelial cells. In a similar fashion, normal neuro-progenitor cells can also differentiate into astrocytes, neurons and oligodendrocytes and transdifferentiate into endothelial cells.