Antiangiogenic Therapy for Glioma

Department of Pharmacology, CNR Institute of Neuroscience, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
Journal of signal transduction 07/2012; 2012(14):483040. DOI: 10.1155/2012/483040
Source: PubMed


Currently, antiangiogenic agents are routinely used for the treatment of patients with glioma. However, despite advances in pharmacological and surgical therapy, glioma remains an incurable disease. Indeed, the formation of an abnormal tumor vasculature and the invasion of glioma cells along neuronal tracts are proposed to comprise the major factors that are attributed to the therapeutic resistance of these tumors. The development of curative therapeutic modalities for the treatment of glioma requires further investigation of the molecular mechanisms regulating angiogenesis and invasion. In this review, we discuss the molecular characteristics of angiogenesis and invasion in human malignant glioma, we present several available drugs that are used or can potentially be utilized for the inhibition of angiogenesis in glioma, and we focus our attention on the key mediators of the molecular mechanisms underlying the resistance of glioma to antiangiogenic therapy.

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    • "Gliomas are highly vascularized tumors [37]. Furthermore, the formation of abnormal tumor vasculature and glioma cell invasion along white matter tracts are proposed to be the major causes of the therapeutic resistance of these tumors [16]. Thus, inhibition of angiogenesis has emerged as a promising strategy for the treatment of brain cancers. "
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    ABSTRACT: Angiogenesis is essential to tumor progression, and the precise imaging of the angiogenic marker vascular endothelial growth factor receptor 2 (VEGFR-2) may provide an accurate evaluation for angiogenesis during a therapeutic response. With the use of molecular magnetic resonance imaging (mMRI), an in vitro cell assay indicated significantly decreased T1 relaxation values when tumor endothelial cells (TEC), which positively expressed VEGFR-2 (Western blot), were in the presence of the VEGFR-2 probe compared to TEC alone (P < 0.001). For in vivo mMRI evaluations, we assessed VEGFR-2 levels in untreated and OKN-007-treated GL261 mouse gliomas. Regarding treatment response, OKN-007 was also able to significantly decrease tumor volumes (P < 0.01) and increase survival (P < 0.001) in treated animals. Regarding in vivo detection of VEGFR-2, OKN-007 was found to significantly decrease the amount of VEGFR-2 probe (P < 0.05) compared to an untreated control group. Fluorescence imaging for the VEGFR-2 probe indicated that there was colocalization with the endothelial marker CD31 in an untreated tumor bearing mouse and decreased levels for an OKN-007-treated animal. Immuno-fluorescence imaging for VEGFR-2 indicated that OKN-007 treatment significantly decreased VEGFR-2 levels (P < 0.0001) when compared to untreated tumors. Immuno-electron microscopy was used with gold-labeled anti-biotin to detect the anti-VEGFR-2 probe within the plasma membrane of GL261 tumor endothelial cells. This is the first attempt at detecting in vivo levels of VEGFR-2 in a mouse GL261 glioma model and assessing the anti-angiogenic capability of an anticancer nitrone. The results indicate that OKN-007 treatment substantially decreased VEGFR-2 levels in a GL261 glioma model, and can be considered as an anti-angiogenic therapy in human gliomas.
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    • "The vascular endothelial growth factor (VEGF) family and its receptors seem to be the central signaling pathway of glioma angiogenesis. The formation of abnormal tumor vasculature and glioma cell invasion are believed to be the major factors responsible for the resistace of gliomas to treatment [12]. The recently demonstrated high vascularity of brain tumors through the secretion of high levels of VEGF – the key mediator of angiogenesis - [12, 13] led to the use of VEGF antagonists as a therapeutic target in glioma therapy [14, 15]. "
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    ABSTRACT: High grade gliomas represent one of the most aggressive and treatment-resistant types of human cancer, with only 1-2 years median survival rate for patients with grade IV glioma. The treatment of glioblastoma is a considerable therapeutic challenge; combination therapy targeting multiple pathways is becoming a fast growing area of research. This review offers an up-to-date perspective of the literature about current molecular therapy targets in high grade glioma, that include angiogenic signals, tyrosine kinase receptors, nodal signaling proteins and cancer stem cells related approaches. Simultaneous identification of proteomic signatures could provide biomarker panels for diagnostic and personalized treatment of different subsets of glioblastoma. Personalized medicine is starting to gain importance in clinical care, already having recorded a series of successes in several types of cancer; nonetheless, in brain tumors it is still at an early stage.
    Current Proteomics 09/2013; 10(3):246-260. DOI:10.2174/1570164611310030007 · 0.64 Impact Factor
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    • "In this context, the poor patient survival is largely attributable to the high invasiveness and accelerated growth of the tumor [9]. It has been reported that invasion and proliferation of glioma cells are angiogenesis-dependent, and that gliomas are among the cancer types with the highest degree of vascularization, which also represents an independent prognostic factor for the disease [9]–[11]. Increased tumor microvascular density (MVD) has been identified as a hallmark in gliomas with a shorter patient survival [12], [13]. "
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    ABSTRACT: Angiogenesis in glioma is associated with the poor prognosis of the disease and closely correlates with the highly invasive phenotype of glioma cells, which represents the most challenging impediment against the currently glioma treatments. Bmi-1, an onco-protein, has been implicated in the progression of various human cancers, including gliomas, whereas its role in glioma angiogenesis remains unclear. Our current study examined the effects of Bmi-1 on glioma angiogenesis in vitro as well as in vivo. We found that overexpression of Bmi-1 enhanced, whereas knockdown of Bmi-1 diminished, the capability of glioma cells to induce tubule formation and migration of endothelial cells and neovascularization in chicken chorioallantoic membrane. In vivo, Bmi-1 overexpression and knockdown, respectively, promoted and inhibited angiogenesis in orthotopically transplanted human gliomas. Furthermore, NF-κB activity and VEGF-C expression was induced by Bmi-1 overexpression, whereas Bmi-1 knockdown attenuated NF-κB signaling and decreased VEGF-C expression. Additionally suppression of NF-κB activity using a specific chemical inhibitor abrogated the NF-κB activation and the pro-angiogenic activities of glioma cells. Together, our data suggest that Bmi-1 plays an important role in glioma angiogenesis and therefore could represent a potential target for anti-angiogenic therapy against the disease.
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