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. 2010:2010:351908.
doi: 10.1155/2010/351908. Epub 2010 Apr 18.

Molecular therapeutic targets for glioma angiogenesis

Shingo Takano  1 , Toshiharu Yamashita, Osamu Ohneda
Affiliations

Molecular therapeutic targets for glioma angiogenesis

Shingo Takano et al. J Oncol. 2010.

Abstract

Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, alpha(v)beta(3) integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs) likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4) results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

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Figures

Figure 1
Figure 1
VEGF localization in gliomas. (a)–(c) Glioblastoma. VEGF localizes in the cytoplasm of the tumor cells and tumor capillary around the necrosis and the tumor periphery. (d) Anaplastic astroctytoma. (e) Diffuse astrocytoma. (f) Normal brain. Original magnification (a, c) ×50, (b, d, e, f) ×200.
Figure 2
Figure 2
VEGF concentration in the various brain tumors.
Figure 3
Figure 3
Tissue factor and VEGF mRNA expression in human glioma samples. Tissue factor expression was frequent and highly observed in glioblastomas associating with VEGF expression.
Figure 4
Figure 4
Thymidine phosphorylase immunohistochemistry in human gliomas. Glioblastoma shows intense immunoreaction for thymidine phosphorylase both in tumor and endothelial cells (a). Diffuse astrocytoma shows no expression (b). Some of the tymidine phosphorylase positive cells (c) are macrophages ((d) serial section of (c)). Thymidine phosphorylase positive glioblastoma (e) reveals a high apoptotic index ((f) serial section of (e)), while Thymidine phosphorylase negative glioblastoma (g) reveals a low apoptotic index ((h) serial section of (g)). Original magnification ×200.
Figure 5
Figure 5
Malignant glioma survival by VEGF/sFlt-1 ratio.
Figure 6
Figure 6
Characterization of thrombospondin-1 transfected U87. Thrombospondin-1 expression was markedly elevated in the transfectant (TSP) compared to vector alone (Neo) and parent U87 (P). Also VEGF expression was decreased in transfectant (TSP).
Figure 7
Figure 7
Inhibition of glioma growth by thrombospondin-1 transfection. The glioma growth is significantly inhibited by thrombospondin-1 transfectant (TSP-1 transfectant) compared to parent U87 and vector alone (Neotransfectant).
Figure 8
Figure 8
Suramin inhibition of bFGF induced endothelial cell urokinase type plasminogen activator activity on gelatin zymogram.
Figure 9
Figure 9
Suramin inhibition of tumor endothelial cell Ki67 labeling.
Figure 10
Figure 10
Elevation of VEGF mRNA expression by ACNU treatment, but not etoposide and CDDP treatment, in human glioma cells (U87 and U251).
Figure 11
Figure 11
Glioma growth inhibition by VEGF antibody, ACNU, and the combination of both treatments with U87 subcutaneous (a) and intracranial (b) model.
Figure 12
Figure 12
Clinical course of a case with recurrent malignant glioma with bevacizumab and CPT11 treatment. After 3 cycles enhanced tumor and perifocal edema is markedly diminished (Bev 2 m). However, after 6 cycles T2 high intense tumors regrow with minimal enhancement (Bev 4 m).
Figure 12
Figure 12
Clinical course of a case with recurrent malignant glioma with bevacizumab and CPT11 treatment. After 3 cycles enhanced tumor and perifocal edema is markedly diminished (Bev 2 m). However, after 6 cycles T2 high intense tumors regrow with minimal enhancement (Bev 4 m).
Figure 13
Figure 13
Malignant glioma survival with hypoxia inducible factor 1α (HIF-1α) expression on immunohistochemistry. HIF-1α expression is a negative prognostic factor.
Figure 14
Figure 14
Antiangiogenic effect of SN38, active metabolite of CPT11. Low dose of SN38 (0.01 and 0.1 μM) inhibited tube formation of HUVEC.
Figure 15
Figure 15
Hypoxia inducible factor 1α expression and hypoxic area with (b, d) and without (a, c) metronomic CPT11 treatment. HIF-1α expression and hypoxic area around the necrosis of glioma tissue decreased with treatment.
Figure 16
Figure 16
Angiogenic factor and chemokine expression in HUVEC and glioblastoma derived endothelial cells (GBMECs). GBMECs show high expression of VEGF, SDF-1, and CXCR7 compared to HUVEC and no expression of CXCR4.
Figure 17
Figure 17
Rich vascular network with EPC-injected glioma. The vessel length of EPC-injected tumor (a) is significantly longer than those of control (b).
Figure 18
Figure 18
EPC homing to glioma vasculature. 11 days after injection of GFP labeled EPCs, EPCs localize lectin labeled glioma vasculature.
See this image and copyright information in PMC

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