CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages

De, Ishani; Steffen, Megan D.; Clark, Paul A.; Patros, Clayton J.; Sokn, Emily; Bishop, Stephanie M.; Litscher, Suzanne J.; Maklakova, Vilena I.; Kuo, John S.; Rodríguez, Fausto J.; Collier, Lara S.

doi:10.1158/0008-5472.can-15-2386

Cited by 75 publications

(55 citation statements)

References 49 publications

(69 reference statements)

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“…Seven genes (CSF1, EIF4EBP1, ESM1, IGFBP1, LPL, SERPINE1 and TP53) that were reported to be downregulated by LGI3 may be upregulated in glioma due to the downregulation of LGI3. In particular, CSF1, EIF4EBP1, SERPINE1 and TP53 (p53) were postulated to be functionally involved in glioma 22,30,32,33. Thus, we hypothesize that LGI3 downregulation in glioma may account for downregulation in glioma of the genes that were shown to be upregulated by LGI3 (IGF1 and PTGS2) and upregulation of the genes that were shown to be downregulated by LGI3 (CSF1, EIF4EBP1, ESM1, IGFBP1, LPL, SERPINE1 and TP53).…”

Section: Discussionmentioning

confidence: 96%

Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma

Kwon¹,

Kim²,

Yun³

2017

OTT

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BackgroundLeucine-rich glioma inactivated 3 (LGI3) is a secreted protein member of LGI family. We previously reported that LGI3 was expressed in brain, adipose tissues and skin, where it played roles as a multifunctional cytokine. We postulated that LGI3 may be involved in cytokine network in cancers.AimThis study aimed to analyze differentially expressed genes in glioma tissues and glioma cohort data to investigate the prognostic role of LGI3 and its receptors.Materials and methodsExpression microarray data from Gene Expression Omnibus and glioma cohort data were analyzed using bioinformatic tools for statistical analysis, protein–protein interactions, functional enrichment and pathway analyses and prognostic association analysis.ResultsWe found that LGI3 and its receptors, ADAM22 and ADAM23, were significantly downregulated in glioma tissues. Eleven upregulated genes and two downregulated genes in glioma tissues were found to be the previously reported LGI3-regulated genes. Protein–protein interaction network analysis showed that 85% of the LGI3-regulated and glioma-altered genes formed a cluster of interaction network. Functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed the association of these genes with hypoxia responses, p53 and Akt signaling and various cancer-related pathways including glioma. Analysis of expression microarray data of glioma cohorts demonstrated that low expression levels of LGI3, ADAM22 and ADAM23 were significantly associated with poor prognosis of glioma.ConclusionThese results propose that LGI3 and its receptors may play a prognostic role in glioma.

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Section: Discussionmentioning

confidence: 96%

Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma

Kwon¹,

Kim²,

Yun³

2017

OTT

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“…In our experiments, targeting the CSF1R ligand CSF1 reduces the total number of bone marrow‐derived macrophages (Evans et al , ; Hume & MacDonald, ). Importantly, effects from targeting CSF1, unlike those achieved when targeting the receptor, should not be confounded by potential activities of the second receptor ligand IL‐34 (De et al , ). Therefore, the use of CSF1R and CSF1 inhibitors in glioma might have differential effects, as the downstream signaling events triggered by CSF1 and IL‐34 are distinct (Chihara et al , ; Barve et al , ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

et al. 2017

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Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro‐inflammatory M1‐like macrophages in the early stages, followed by in situ repolarization to M2‐like macrophages, which produced VEGF‐A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti‐CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences.

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“…(4), for simplicity we do not describe the two types separately. CSF1 is overexpressed in human glioblastomas (36) and can be synthesized and produced in both cell-surface form and secreted form (37). The secreted CSF1 by glioma cells then diffuses into the microenvironment.…”

Section: Pde Modelmentioning

confidence: 99%

A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy

Zheng

Bao

Zhao

et al. 2018

Molecular Cancer Therapeutics

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The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor-targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies. .

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CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages

Cited by 75 publications

References 49 publications

Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma

Leucine-rich glioma inactivated 3: integrative analyses support its prognostic role in glioma

Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy

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