The disturbed blood–brain barrier in human glioblastoma

Wolburg, Hartwig; Noell, Susan; Fallier‐Becker, Petra; Mack, Andreas F.; Wolburg‐Buchholz, Karen

doi:10.1016/j.mam.2012.02.003

Cited by 222 publications

(201 citation statements)

References 88 publications

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“…A previous study from our lab showed that antibodies successfully cross the blood-brain barrier (BBB) and penetrate into the TME; the loss of BBB integrity associated with GBM growth may further support this process. [59][60][61][62][63] A preliminary analysis of Gr-1 antibody-treated mice showed that the efficacy of depletion lasted for approximately 4 days. Therefore, to ensure the maintenance of TK/Flt3L-induced tumor-specific T cell proliferation, we administered the antibody so that MDSCs would be eliminated from the GBM TME around the peak of the T cell response, which occurs 7 days after the administration of gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

et al. 2017

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Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumorinfiltrating immune cells. These cells express IL-4Ra, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.

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Section: Discussionmentioning

confidence: 99%

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

et al. 2017

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“…The poor permeability of the BBB is one of the reasons why systemic therapies, typically effective in other types of cancer, have been less efficacious in treating primary and metastatic brain malignancies (19). However, high-grade gliomas induce several alterations on tumorassociated vasculature, including the formation of fenestrations, disruption of tight junctions, alterations in thickness of the subendothelial basal lamina, and increased perivascular space (20). First line treatment for glioblastomas, which includes maximal surgical resection and radiotherapy, further disrupt the integrity of the BBB (21,22).…”

Section: Discussionmentioning

confidence: 99%

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Yang

Hernandez

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ2 = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.

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“…Briefly, HBVECs and GBM-ECs (passaged 2-3 times) were harvested using trypsin in EGM2. Next, 600 ml EGM2 medium was added to the lower chambers, while 1x10 5 HBVECs or GBM-ECs were plated in the upper chambers in EGM2. After 4 h of incubation, cells on the bottom of the Transwell membrane were fixed with 4% paraformaldehyde at 37˚C for 20 min and stained with 1% crystal violet at 37˚C for 10 min; the non-migrating cells in the upper chamber were removed with blunt-end swabs.…”

Section: Ec Low-density Lipoprotein (Ldl) Uptakementioning

confidence: 99%

“…A key feature of GBMs is the extensive network of abnormal vasculature, characterized by glomeruloid structures and endothelial hyperplasia (4). Due to the location of GBM in the brain, the primary clinical problem is the edematous swelling and dramatic increase of intracerebral pressure caused by the disrupted blood brain barrier (BBB) and leaky blood vessels (5,6). A current therapeutic approach against GBMs is targeted against this vascularization process (7).…”

Section: Introductionmentioning

confidence: 99%

PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas

Zhai

Liang

et al. 2017

Oncol Lett

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Abstract. Glioblastomas are brain tumors with extensive vascularization that are associated with tumor malignancy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is activated in endothelial cell tumors, although its exact function in glioblastoma neovascularization is poorly characterized. The present study identified that endothelial cells derived from human glioblastomas exhibit increased permeability and motility compared with normal brain vascular endothelial cells. Furthermore, the phosphorylation of AKT was significantly induced in glioblastoma-derived endothelial cells and glioblastoma vessels. To the best of our knowledge, the present study demonstrated for the first time that the cell-cell adhesion junction protein Afadin is phosphorylated and re-localized in glioblastoma-derived endothelial cells, and the phosphorylation and re-localization of Afadin is PI3K/AKT pathway-dependent. AKT-mediated phosphorylation and re-localization of Afadin may be critically involved in the modulation of brain endothelial permeability and migration. Therapies targeting the PI3K/AKT/Afadin pathway may therefore be beneficial for reducing the angiogenic potential of glioblastoma.

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The disturbed blood–brain barrier in human glioblastoma

Cited by 222 publications

References 88 publications

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas

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The disturbed blood–brain barrier in human glioblastoma

Cited by 222 publications

References 88 publications

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

Targeting CD146 with a 64 Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas

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Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas