Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Jones, Terreia S.; Holland, Eric C.

doi:10.1038/onc.2011.398

Cited by 44 publications

(33 citation statements)

References 114 publications

(118 reference statements)

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“…The pathologic triad of this disease includes the highly proliferative capacity of the tumor cells, their borderless invasive ability, and tumor neoangiogenesis (1). The invasive nature of glioblastomas prevents complete surgical removal and renders them resistant to temozolomide-based chemotherapy, radiation, and a combination of both (2). Consequently, the median overall survival of patients following diagnosis is just 15 months and has not improved significantly over the past 30 years (1, 3).…”

Section: Introductionmentioning

confidence: 99%

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Chikano

Domoto

Furuta

et al. 2015

Molecular Cancer Therapeutics

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The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3b (GSK3b), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3b compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3b also contributes to the highly invasive nature of glioblastoma. The effects of GSK3b inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3b attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3b as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo-and radioresistance. Mol Cancer Ther; 14(2); 564-74. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Chikano

Domoto

Furuta

et al. 2015

Molecular Cancer Therapeutics

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“…Gliomas are easy to be recurrent even after extensive surgical resection combined with radio-and chemotherapy treatment (2,3). In recent years, targeted gene therapy against gliomas has attracted increasing attention (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

Peng

et al. 2015

Oncology Reports

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Abstract. Bone marrow mesenchymal stem cells (BMSCs) have the ability of migrating towards glioma tissue. However, this migratory behavior remains to be elucidated. The aim of this study was to define the role of integrin α4 in the motility of BMSCs towards glioma. The role of integrin α4 in the migration of BMSCs towards glioma was evaluated using an in vitro migration assay with the application of a specific integrin α4-blocking antibody. The effect of glioma conditioned medium (CM) on the integrin α4 expression level of BMSCs was assessed by RT-PCR, immunocytochemistry and western blot analysis. BAY11-7082, LY294002, SB203580, PD98059 and SP600125 were used to investigate the role of NF-κB, PI3K, p38 MAPK, MEK and JNK in the above process. In addition, the role of NF-κB in the tropism of BMSCs towards glioma was also evaluated using the in vitro model. The migration of BMSCs towards glioma CM was attenuated by blocking integrin α4. The stimulation of glioma CM increased integrin α4 expression of BMSCs. Furthermore, the inhibition of NF-κB and PI3K decreased the glioma-induced integrin α4 upregulation on BMSCs. Inhibition of NF-κB decreased the number of migrating BMSCs towards gliomas. Glioma cells induced the migration of BMSCs by promoting the expression of integrin α4. NF-κB and PI3K contributed to the signal transduction of this process. Similar to PI3K, NF-κB is associated with the regulation of BMSCs migration toward glioma. Thus, these results may be useful to elucidate the mechanism involved in the glioma-induced migration of BMSCs.

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“…However, it has been proposed that Dex might improve peritumoral edema through its anti-inflammatory effect or by inhibiting microglial cells proliferation and pro-inflammatory cytokine production [68,73]. In rat glioma, DEX was found to decrease microglial cell proliferations infiltration into the tumor [73].…”

Section: Corticosteroids Decrease Microglial Cell Number and M2-like mentioning

confidence: 99%

“…However, it has been proposed that Dex might improve peritumoral edema through its anti-inflammatory effect or by inhibiting microglia cells [68,73]. Microglial cells are the dominant immune cells in the brain, comprising 5-20% of total glial cells and up to approximately 35% in the glioma [95,96].…”

Section: The Anti-proliferation Properties Of Dexmentioning

confidence: 99%

“…ALL, acute lymphoblastic leukemia; AML, actute myloid leukemia; AZA, azathiopurine; MP, mercaptopurine; MDS, Myelodysplasic syndrome PNET, primitive neuroectodermal tumor in central nervous system; PTLD, post-transplantation lymphoproliferative disease ∏ These three patients received azathiopurine [2,68]. Despite the therapeutic advancement, the estimated overall survival is 3 years for approximately only 7% of the patients [2].…”

Section: Thiopurines and Incidence Of Secondary Brain Tumorsmentioning

confidence: 99%

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Glioma: A Tale of Corticosteroids, Thiopurines and Proposed Novel AntiGlioma Small Molecules

Ahmed¹

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Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Cited by 44 publications

References 114 publications

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

Glioma: A Tale of Corticosteroids, Thiopurines and Proposed Novel AntiGlioma Small Molecules

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