scholarly journals Primary human macrophages are polarized towards pro-inflammatory phenotypes in alginate hydrogels

2019 ◽  
Author(s):  
Derfogail Delcassian ◽  
Anna A. Malecka ◽  
Donaldson Opoku ◽  
Virginia Palomares Cabeza ◽  
Catherine Merry ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Polarization State ◽  
Fold Increase ◽  
M2 Macrophages ◽  
Human Macrophages ◽  
Culture Systems ◽  
Wide Range ◽  
Alginate Hydrogels ◽  
Planar Substrates

AbstractDysregulated macrophage function is implicated in a wide range of disorders. In vitro hydrogel culture systems are often used as matrices to model and explore the effect of various external stimuli on macrophage polarization and behaviour. Here, we show that 3D alginate hydrogels are not “macrophage inert” and instead help to direct the maturation of primary human macrophages towards specific phenotypes. We compared polarization of M1-like and M2-like cells activated on planar substrates or in 3D alginate hydrogels (with or without adhesion motifs (RGD)). We show that culture in 3D alginate systems selectively alters M2 polarisation following activation; cells show a 2.6-fold increase in CD86 expression compared to cells matured on planar controls, and increase IL1β cytokine secretion even in response to an M2-like stimulus (LPS alone in the absence of IFNγ). Our results suggest that alginate materials may intrinsically stimulate M2 macrophages to acquire a unique polarization state (resembling M2b), characterized by enhanced expression of CD86 and IL1β secretion while retaining low IL12 and high IL10 secretion typical for M2 macrophages. This has important implications for researchers using alginate hydrogels to study macrophage behavior in culture and co-culture systems, as alginate itself may induce direct phenotypic changes independently or in conjunction with other stimuli.

scholarly journals TMIC-51. GBP1 RECRUITS MACROPHAGES TO PROMOTE GLIOBLASTOMA GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi259-vi259
Author(s):  
Lili Chen ◽  
Ming Li
Keyword(s):  
Macrophage Polarization ◽  
Tumor Development ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Orthotopic Mouse Model ◽  
Ccl2 Expression ◽  
Molecule Inhibitor ◽  
Signaling Axis ◽  
And Migration

Abstract Guanylate binding protein 1 (GBP1) is an interferon-inducible large GTPase which plays a key role in tumor development, but the molecular mechanism is poorly understood. Here we investigated whether GBP1 could influence the tumor microenvironment in glioblastoma, the most common and malignant brain tumor. We found that forced expression of GBP1 in glioblastoma cells induced macrophage polarization toward an M2 phenotype via upregulating Chemokine (C-C motif) ligand 2 (CCL2). CCL2 acted via its receptor C-C chemokine receptor 2 (CCR2) to enhance macrophage cell migration in vitro. The M2 macrophages in turn promoted glioblastoma cell proliferation and migration. The orthotopic mouse model showed that GBP1 recruited M2 macrophages into tumor to promote glioblastoma progression, and targeting CCL2/CCR2 signaling axis with a small molecule inhibitor RS504393 led to decreased macrophage attraction and M2 polarization and a significant tumor growth retardation and prolonged survival of tumor-bearing mice. Clinically, GBP1 expression positively correlated with M2 macrophage numbers and CCL2 expression in glioblastoma. Taken together, our results reveal that GBP1 modulates the tumor immune microenvironment through CCL2 induction to promote glioblastoma infiltrating growth, and targeting tumor-associated macrophages may represent a new therapeutic strategy against glioblastoma.

scholarly journals Macrophage Polarization and Osteoporosis: A Review

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2999
Author(s):  
Joseph Muñoz ◽  
Neda S. Akhavan ◽  
Amy P. Mullins ◽  
Bahram H. Arjmandi
Keyword(s):  
Bone Resorption ◽  
Bone Mineralization ◽  
Macrophage Polarization ◽  
Polarization State ◽  
M2 Macrophages ◽  
Cytokines And Chemokines ◽  
Polarization States ◽  
Classically Activated Macrophages ◽  
Cost Efficient ◽  
Alternatively Activated

Over 200 million people suffer from osteoporosis worldwide. Individuals with osteoporosis have increased rates of bone resorption while simultaneously having impaired osteogenesis. Most current treatments for osteoporosis focus on anti-resorptive methods to prevent further bone loss. However, it is important to identify safe and cost-efficient treatments that not only inhibit bone resorption, but also stimulate anabolic mechanisms to upregulate osteogenesis. Recent data suggest that macrophage polarization may contribute to osteoblast differentiation and increased osteogenesis as well as bone mineralization. Macrophages exist in two major polarization states, classically activated macrophages (M1) and alternatively activated macrophage (M2) macrophages. The polarization state of macrophages is dependent on molecules in the microenvironment including several cytokines and chemokines. Mechanistically, M2 macrophages secrete osteogenic factors that stimulate the differentiation and activation of pre-osteoblastic cells, such as mesenchymal stem cells (MSC’s), and subsequently increase bone mineralization. In this review, we cover the mechanisms by which M2 macrophages contribute to osteogenesis and postulate the hypothesis that regulating macrophage polarization states may be a potential treatment for the treatment of osteoporosis.

scholarly journals Abnormal Macrophage Polarization in Patients with Myelodysplastic Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Gaochao Zhang ◽  
Liyan Yang ◽  
Yu Han ◽  
Haiyue Niu ◽  
Li Yan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Macrophage Polarization ◽  
Control Group ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Tnf Α ◽  
Bone Marrow Microenvironments ◽  
Medical University

Background. This study is aimed at assessing the subsets of bone marrow macrophages in patients with myelodysplastic syndrome (MDS) and exploring the role of macrophages in the pathogenesis of MDS. Methods. Thirty-eight newly diagnosed MDS patients were enrolled in the Department of Hematology of General Hospital of Tianjin Medical University from June 2015 to June 2016. Bone marrow monocytes and macrophage subsets (M1/M2) were detected in patients with MDS and normal controls by flow cytometry. M1 macrophages were cultured in vitro, and the expression of IL-1β and TNF-α mRNA was measured using real-time polymerase chain reaction. Results. Compared with the normal control group, the proportion of bone marrow monocytes was higher ( 2.11 ± 0.93 % vs. 3.66 ± 3.38 % ), and the mean fluorescence intensity of surface molecule CD14 was lower in the higher-risk (HR) MDS group ( 639.05 ± 359.78 vs. 458.26 ± 306.72 , p < 0.05 ). The ratio of M2 macrophages to monocytes was higher in patients with HR-MDS ( 1.82 ± 2.47 % vs. 3.93 ± 3.81 % , p < 0.05 ). The ratio of M1 to M2 macrophages was lower in the HR-MDS group ( 3.50 ± 3.22 vs. 1.80 ± 0.88 , p < 0.05 ). The expression of IL-1β and TNF-α mRNA in M1 macrophages was significantly lower in the MDS group ( p < 0.05 ). Conclusions. Patients with MDS had abnormal macrophage polarization, which may be involved in the alteration of bone marrow microenvironments.

scholarly journals Targeting M2 Macrophages Alleviates Airway Inflammation and Remodeling in Asthmatic Mice via miR-378a-3p/GRB2 Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Qiujie Wang ◽  
Luna Hong ◽  
Ming Chen ◽  
Jiangting Shi ◽  
Xiaoling Lin ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Alveolar Macrophages ◽  
Target Gene ◽  
Macrophage Polarization ◽  
Growth Factor Receptor ◽  
Luciferase Reporter ◽  
M2 Macrophages ◽  
Mirna Profiling ◽  
M2 Polarization

Background: Asthma is a complex respiratory disease characterized by airway inflammation and remodeling. MicroRNAs (miRNAs) mediate various cellular processes including macrophage polarization and play an important role in the pathogenesis of asthma. In present study, we aimed to screen miRNA profiling involved in macrophage polarization and investigate its possible functions and mechanisms.Methods: An OVA-sensitized mouse model was established and 2-chloroadenosine (2-CA) was used to interfere with macrophages. The airway inflammation and remodeling were assessed. The identification and function of M2 alveolar macrophages were assessed by flow cytometry, RT-qPCR, arginase activity and co-culture experiment. Microarray screening was used to select miRNAs which were related to macrophage polarization and RNA interference (RNAi) technique was performed to confirm the function of the selected miRNA and its target gene.Results: Alveolar macrophages of asthmatic mice showed significant M2 polarization. 2-CA alleviated airway inflammation and remodeling as well as M2 polarization. In vitro, IL-4-induced M2 macrophages promoted the proliferation of α-SMA-positive cells. And miRNA profiling showed a remarkable increased expression of miR-378a-3p in IL-4 induced M2 macrophages. Dual luciferase reporter assay confirmed growth factor receptor binding protein 2 (GRB2) was a target gene of miR-378a-3p. A miR-378a-3p inhibitor and knockdown of GRB2 repolarized alveolar macrophages from M1 to M2 phenotype.Conclusion: Our findings suggest that miR-378a-3p/GRB2 pathway regulates the polarization of alveolar macrophages which acts as a potential therapeutic target for airway inflammation and remodeling in asthma.

scholarly journals Luteolin Regulates the Differentiation of Regulatory T Cells and Activates IL-10-Dependent Macrophage Polarization against Acute Lung Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Ke Xie ◽  
Yu-sen Chai ◽  
Shi-hui Lin ◽  
Fang Xu ◽  
Chuan-jiang Wang
Keyword(s):  
T Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Models ◽  
Mononuclear Cells ◽  
Macrophage Polarization ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Treg Differentiation

Objectives. Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation. Methods. In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined. Results. Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4+CD25+FOXP3+ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages. Conclusions. Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4+CD25+FOXP3+ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from naïve CD4+ T cells may be a potential mechanism for regulating IL-10 production.

Changes in alpha-7 nicotinic acetylcholine receptor and macrophage polarization state participate in the regulation of cervical remodeling in pregnant rats†

2019 ◽  
Author(s):  
Jinying Yang ◽  
Yumian Lai ◽  
Juanhua Chen ◽  
Baohua Lin ◽  
Bei Zhou ◽  
...  
Keyword(s):  
Western Blotting ◽  
Macrophage Polarization ◽  
Polarization State ◽  
M2 Macrophages ◽  
Pregnant Rats ◽  
M1 Macrophages ◽  
Nicotinic Acetylcholine ◽  
Immunohistochemistry Staining ◽  
Cervical Remodeling ◽  
Alpha 7

Abstract To test the hypothesis that changes in alpha-7 nicotinic acetylcholine receptor (α7nAChR) expression on macrophages and macrophage polarization participate in cervical remodeling during normal pregnancy, pregnant rats from gestational days (GDs) 14, 16, 18, 20, and 22 were used in the present study. The expression of α7nAChR on macrophages and the numbers of M1 and M2 macrophages were detected by double immunofluorescence staining. The levels of α7nAChR and collagens were detected by western blotting. M1 markers (inducible nitric oxide synthase and inflammatory cytokines) and M2 markers (arginase 1, anti-inflammatory cytokines) were detected to evaluate the macrophage polarization state by immunohistochemistry staining, western blotting, and the enzyme-linked immunosorbent assay. Matrix metalloproteinase 9 (MMP-9) expression was determined by immunohistochemistry staining and western blotting. We found that the α7nAChR expression on macrophages significantly decreased on GD22 compared to GDs 14, 16, 18, and 20. There was an increased number of M1 macrophages and decreased number of M2 macrophages in late pregnancy. The expression of M1 macrophage biomarkers was much higher on GDs 20 and 22 than on GDs 14, 16, and 18, but expression of M2 biomarkers decreased on GDs 20 and 22 compared to GDs 14, 16, and 18. MMP-9 expression was higher on GD22 than on GDs 14, 16, 18, and 20, and collagen expression significantly decreased on GDs 18, 20, and 22 compared to GD14. Our results indicated that the decreased expression of α7nAChR and increased number of M1 macrophages are associated with cervical remodeling.

scholarly journals Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yohei Kawai ◽  
Yuji Narita ◽  
Aika Yamawaki-Ogata ◽  
Akihiko Usui ◽  
Kimihiro Komori
Keyword(s):  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Gene Expressions ◽  
Arginase 1 ◽  
M2 Macrophage Polarization

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

Medicinal Plants As Natural Polarizers of Macrophages: Phytochemicals and Pharmacological Effects

2019 ◽  
Vol 25 (30) ◽  
pp. 3225-3238 ◽  
Author(s):  
Amirhossein Davoodvandi ◽  
Roxana Sahebnasagh ◽  
Omid Mardanshah ◽  
Zatollah Asemi ◽  
Majid Nejati ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Expression Patterns ◽  
Inflammatory Cells ◽  
Natural Compounds ◽  
M2 Macrophage ◽  
Pharmacological Effects ◽  
M2 Macrophages ◽  
Pharmacological Agents ◽  
Wide Range ◽  
Anti Inflammatory

Macrophages are one of the crucial mediators of the immune response in different physiological and pathological conditions. These cells have critical functions in the inflammation mechanisms that are involved in the inhibition or progression of a wide range of diseases including cancer, autoimmune diseases, etc. It has been shown that macrophages are generally divided into two subtypes, M1 and M2, which are distinguished on the basis of their different gene expression patterns and phenotype. M1 macrophages are known as pro-inflammatory cells and are involved in inflammatory mechanisms, whereas M2 macrophages are known as anti-inflammatory cells that are involved in the inhibition of the inflammatory pathways. M2 macrophages help in tissue healing via producing anti-inflammatory cytokines. Increasing evidence indicated that the appearance of different macrophage subtypes is associated with the fate of diseases (progression versus suppression). Hence, polarization of macrophages can be introduced as an important venue in finding, designing and developing novel therapeutic approaches. Albeit, there are different pharmacological agents that are used for the treatment of various disorders, it has been shown that several natural compounds have the potential to regulate M1 to M2 macrophage polarization and vice versa. Herein, for the first time, we summarized new insights into the pharmacological effects of natural compounds on macrophage polarization.

Macrophage Polarization and Acquired Resistance to Rituximab in CNS Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3749-3749
Author(s):  
Cigall Kadoch ◽  
Valerie D. Wong ◽  
Tara Rambaldo ◽  
William Hyun ◽  
Clifford Lowell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Macrophage Polarization ◽  
Acquired Resistance ◽  
Fold Increase ◽  
Cns Lymphoma ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Non Hodgkin Lymphoma ◽  
Macrophage Subpopulations ◽  
M2 Phenotype

Abstract Abstract 3749 Poster Board III-685 Macrophages are a critical component of anti-tumor immunity but may be subverted from the classically-activated, or M1 phenotype, which mediates tumor elimination, to an alternatively-activated, M2 phenotype, which promotes tumor progression. Interleukin-4 (IL-4) signaling is a pivotal regulator of macrophage polarization to the M2 phenotype. The efficacy of rituximab appears to be mediated predominantly by antibody-dependent cellular cytotoxicity (ADCC) with tumor-associated macrophages being the dominant effector cell. We hypothesize that the phenotype of tumor-associated macrophages (M1 vs. M2) may be a potential determinant of rituximab efficacy or resistance. Relevant to this hypothesis is our demonstration of the intratumoral expression of IL-4 by CNS lymphoma (Blood, 2006; Clin Cancer Res., 2009) as well as our observation that the M2 polarization of macrophages by IL-4 treatment in vitro (18 h) results in an 8-fold decrease in rituximab-mediated ADCC of Raji lymphoma cells compared to ADCC-mediated by naïve or M1 polarized macrophages (p<0.001). There is an extreme paucity of molecular information regarding the role and phenotype of tumor macrophages in non-Hodgkin lymphoma in general, including CNS lymphoma. While macrophages from the cerebrospinal fluid (CSF) are routinely quantified in cytospin analyses, to date there is no established information regarding the phenotype and state of differentiation of macrophages within the leptomeningeal compartment. We have developed a novel flow-cytometry-based protocol for the isolation and phenotypic characterization of macrophages from the CSF of patients with CNS lymphoma. We have used candidate markers of M2 differentiation based upon our gene expression studies of CD14+ activated CSF macrophages, including CD206 and Factor XIII (each of which have previously been shown to be induced in macrophages upon IL-4 stimulation). We have identified M1 differentiation of CSF CD14+ macrophages by high fluorescence when incubated with DAF-FM diacetate, a cell-permeable marker of nitric oxide synthase (iNOS). Using flow-cytometry to evaluate the relative expression of DAF-FM and CD206, we demonstrate the presence of at least four subpopulations of activated macrophages in the CSF of CNS lymphoma patients. M1 macrophages, which highly express iNOS are denoted as DAF-FM(+)/CD206(-). M2 macrophages, which weakly express iNOS but which highly express CD206 are denoted as DAF-FM (-)/CD206(+). In addition, we have detected a mixed phenotype with features of both M1 and M2 macrophages, DAF-FM(+)/CD206(+), which we have termed dual-activated. A fourth subpopulation of activated macrophages within the CSF do not express iNOS or CD206. Thus far, CSF macrophage subpopulations have been characterized and sorted from thirty-five subjects: 18 patients with CNS lymphoma and 17 control subjects with non-neoplastic conditions. We demonstrate for the first time the association of M2 macrophages within the CSF with the pathogenesis of CNS lymphoma: there was a greater than six-fold increase in the proportion of macrophages with M2 features in immunocompetent subjects with CNS lymphoma compared to controls (p<0.001). By contrast, the proportion of macrophages with M1 features was similar between lymphoma and controls. In addition, we reproducibly detected an increase in the ratio of M1:M2 macrophages which correlated with therapeutic response to intrathecal methotrexate or cytarabine (within 94 h) in CNS lymphoma patients. By contrast, the intraventricular administration of rituximab was reproducibly associated with a greater than three-fold increase in the relative ratio of M2:M1 macrophages which was sustained compared to macrophages analyzed pre-intrathecal rituximab (p<0.001). In each of four cases, increases in M2 macrophage polarization anticipated the onset of intrathecal rituximab resistance and tumor progression. We believe this to be the first application of flow-cytometry to define the polarization states of intratumoral macrophages in non-Hodgkin lymphoma as well as the first description of dynamic changes in macrophage phenotypes during the evolution of resistance to rituximab therapy. The elucidation of distinct macrophage subpopulations based upon the expression of candidate markers of M1 vs. M2 phenotype may provide insight into tumor pathogenesis and prognosis. Disclosures: Off Label Use: While we describe the use of intrathecal administration of rituximab in patients with recurrent CNS and intraocular lymphomaa, the focus of our study is on the relationship between M2 macrophage polarization and the pathogenesis of CNS lymphoma as well as the potential relationship of macrophage polarization to acquired resistance to rituximab in CNS lymphoma patients.

scholarly journals Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 44 ◽  
Author(s):  
Seamus Caragher ◽  
Anthony J. Chalmers ◽  
Natividad Gomez-Roman
Keyword(s):  
Mouse Models ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Current Standard ◽  
Meaningful Improvement ◽  
Nutrient Sources ◽  
Culture Systems ◽  
Novel Treatments ◽  
Wide Range

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

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