Article

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

ABSTRACT 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.

Download full-text

Full-text

Available from: Valentina Cea, Jun 30, 2015
0 Followers
 · 
201 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 01/2013; 8(1):e55527. DOI:10.1371/journal.pone.0055527 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is associated with tumor development and progression in a variety of epithelial carcinomas, while its expression and role in gliomas have not been considered. The aim of the study was to investigate TROP2 expression in malignant gliomas with different World Health Organization (WHO) classification and its correlation with tumor proliferation and angiogenesis. Immuohistochemistry was used to determine TROP2 and Ki-67 expression and microvessel density (MVD) in tumor specimens and normal brain tissues from 69 glioma patients and the relationship between TROP2 and Ki-67 and MVD was investigated. Immunohistochemistry results showed that the TROP2 expression was found in 59 (85.5 %) of the 69 tumor specimens, but no expression in normal brain tissues. Furthermore, TROP2 expression is significantly higher in WHO grade III (P = 0.025) and WHO grade IV (P = 0.011) gliomas than in WHO grade II gliomas. TROP2 expression correlates with Ki-67 (r = 0.676, P = 0.012) and MVD (r = 0.365, P = 0.035), but not with gender or age in human gliomas. These results suggested that the TROP2 correlated with malignancy, proliferation and angiogenesis in human gliomas. This is the first study describing TROP2 expression in gliomas and its proliferation and angiogenesis-related characteristic may serve as a potential therapeutic target for glioma treatment.
    Neurological Sciences 02/2013; 34(10). DOI:10.1007/s10072-013-1326-8 · 1.50 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Journal of Molecular Medicine 03/2013; 91(4). DOI:10.1007/s00109-013-1019-z · 4.74 Impact Factor