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Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Despite new knowledges on the genetic characteristics, conventional therapy for GBM, tumor resection followed by radiotherapy and chemotherapy using temozolomide is limited in efficacy due to high rate of recurrence. GBM is indeed one of the most complex and difficult cancer to treat mainly due to its highly invasive properties and the standard treatments are thus rarely curative. Major challenges in the treatment of GBM are the limitation of irreversible brain damage, the infiltrative part of the tumor which is the ultimate cause of recurrence, the difficulty of identifying tumor margins and disseminated tumor cells, and the transport across the blood-brain barrier in order to obtain a sufficient therapeutic effect for pharmalogical agents. Considering these limitations, this review explores the in vivo potential of metal-based nanoparticles for hyperthermia, radiotherapy and photodynamic therapy. This article describes and clearly outlines the recent in vivo advances using innovative therapeutic metallic nanoparticles such as iron oxide, silver, gadolinium and gold nanoparticles., (Copyright © 2018. Published by Elsevier B.V.)

Aims: Glioma initiating cells (GICs) represent a subpopulation of tumor cells endowed with self-renewal and multilineage differentiation capacity but also with innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in glioma patients., Materials and Methods: In this work, GICs were obtained from two patient-derived high-grade gliomas xenograft model, expressing differently EGFR. GICs were exposed to anti-EGFR monoclonal antibody cetuximab during 48h in 1% or 21% oxygen tension. Cell viability and self-renewal capacity were then evaluated as well as their angiogenic properties., Key Findings: GICs were sensitive to cetuximab only in normoxic condition whatever the EGFR status. Nevertheless, under hypoxia cetuximab was able to decrease the self-renewal capacity as well as the expression of CD133 while expression of GFAP increased. Moreover, cetuximab decreased the effect of GICs on endothelial cell migration under hypoxia., Significance: Consequently, anti-EGFR therapy can be envisaged to target specifically GICs in order to limit the tumor recurrence., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Free doxorubicin (DXR) is not currently used to treat brain tumors because (i) the blood-brain barrier limits the drug deposition into the brain (ii) lethal toxic effects occur when combined with radiation therapy. Since encapsulation of DXR within liposomal carriers could overcome these drawbacks, the present study aimed at evaluating the radiosensitizing properties of non-pegylated (NPL-DXR) and pegylated (PL-DXR) liposomal doxorubicin on orthotopic high-grade glioma xenografts (U87)., Methods: DXR accumulation in brain tissues was assessed by a high-performance liquid chromatography method and antitumor efficacy was evaluated by mice survival determination., Results: We showed that encapsulation of DXR ensured a preferential deposition of DXR in tumoral tissue in comparison with normal brain tissue: the best AUC tumor tissue/AUC normal tissue ratio depended greatly on the schedule. Overall, thanks to the optimization of the delivery schedule, we demonstrated a radiosensitizing effect for both liposomal DXR without toxicity of this combination on the U87 human malignant glioma orthotopic xenografts., Conclusion: This study shows that the use of nanocarriers, allowing targeting of intracerebral tumor, renders relevant the combination of anthracyclin with radiation therapy to treat brain tumors, opening a new field of therapeutic applications. However, our results point out that, for each new delivery system, the administration schedules need to be rigorously optimized.

Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α(5) β(1) integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of α(5) β(1) integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls α(5) β(1) integrin expression and to determine if a negative correlation between caveolin-1 and α(5) β(1) integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFβ/TGFβRI/Smad2 pathway which in turn induced the expression of α(5) β(1) integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of α(5) β(1) integrins and TGFβRI were the most sensitive to a α(5) β(1) integrin antagonist and a TGFβRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of α(5) β(1) integrin and TGFβRI or high levels of caveolin-1 but low levels of α(5) β(1) integrin and TGFβRI. In conclusion, caveolin-1 controls α(5) β(1) integrin expression through the TGFβ/TGFβRI/Smad2 pathway. The status of caveolin-1/α(5) β(1) integrins/TGFβRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFβ or anti-α(5) β(1) integrin therapies., (Copyright © 2011 UICC.)

Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of α5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the α5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, α5β1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high α5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between α5β1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that α5β1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of α5β1 integrin.

Purpose: Ferumoxtran-10 belongs to the Ultra Small Particles of Iron Oxide (USPIO) class of contrast agents and induces delayed tumor enhancement in brain tumors, reflecting the trapping of iron oxide particles by the macrophages and activated microglia. The aim of the study was to compare Ferumoxtran-10 contrast enhancement in four human high-grade glioma xenograft models (TCG2, TCG3, TCG4, and U87) with different growing profiles., Materials and Methods: Fragments of human malignant glioma were orthotopically xenografted into the brain of four groups of nude mice. All mice underwent a MRI examination 24 h after intravenous administration of Ferumoxtran-10 (axial T1 SE weighted MR images). The contrast enhancement observed in the different tumor types was measured and was correlated to in vivo tumor growth and to histological parameters, such as proliferative tumor cell fraction, apoptosis, vascular density, and Perls' staining score., Results: A good relationship was observed: (a) between tumor-to-background contrast and proliferative index, (b) between tumor-to-background contrast and tumor growth, and (c) between tumor-to-background contrast and Perls' staining score. The registered MR enhancement contrasts were not influenced by apoptotic index and by vascular density in these experimental xenografts., Conclusions: Tumor contrast enhancement 24 h after intravenous Ferumoxtran-10 administration seems to be well correlated to tumor proliferative index and tumor growth and could be used as an indirect marker of tumor proliferation.

Purpose: Several studies reported that prolongation of overall treatment time of fractionated radiotherapy reduces the chance of tumor control. In the present study, we hypothesize that combining topotecan with irradiation could compensate for this detrimental time effect on the radioresponse. Therefore, we investigated the efficiency of different schedules of topotecan (TPT), radiotherapy (RT) or concomitant combination TPT + RT., Methods and Materials: Experiments were performed in two human high-grade glioma xenograft models (U87 and GBM Nan1). TPT and RT were delivered at a total dose of 3 mg/kg and 40 Gy, respectively. For the TPT + RT groups, TPT was injected 5 min before radiation. Total radiation doses were delivered in 5, 10, 20, or 30 fractions over 1, 2, 4, or 6 weeks, respectively. The efficiency of TPT, RT, and TPT + RT was evaluated by tumor growth delay (TGD)., Results: At this low total dose, and independent of the schedule, no efficacy was found in TPT-treated glioma xenografts. Conversely, radiotherapy-induced antitumor effect decreased with prolongation of treatment time. For TPT + RT combination, antitumor activity was not influenced by schedule, and tumor response was always comparable to those measured for the shortest and the most efficient irradiation schedule (i.e. 1 week). When treatment was delivered over 4 or 6 weeks in U87 glioma xenografts, therapeutic enhancement ratios reached 2.6 and 3.7, respectively. This indicated that the interaction between ionizing radiation and topotecan was synergistic., Conclusion: The present study demonstrated that concomitant topotecan can compensate for the detrimental effect of treatment time protraction on radiotherapy efficacy in two malignant glioma xenografts.