CXCR4 increases <i>in-vivo</i> glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study

Yadav, Viveka Nand; Zamler, Daniel; Baker, Gregory J.; Kadiyala, Padma; Erdreich‐Epstein, Anat; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, María G.; Löwenstein, Pedro R.

doi:10.18632/oncotarget.13295

Cited by 74 publications

(63 citation statements)

References 52 publications

(53 reference statements)

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“…Glioma cells are recruited to the perivascular space around blood vessels by chemoattractants like bradykinin, which is produced by endothelial cells (16). Also, overexpression of chemokine receptors on glioma cells has been associated with perivascular invasion (17). Cell movement along white matter tracts, a second known route of glioma cell invasion, is mediated by a variety of proteins called axonal guidance molecules (see the section "Axonal Guidance Molecules"), which act as attracting or repelling factors.…”

Section: Patterns Of Glioma Cell Infiltrationmentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

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Gliomas are the most common intracranial tumors in humans. The most malignant among these tumors is glioblastoma (GBM), with an incidence of 3-5 out of 100,000 persons in Western countries. GBM arises either de novo (primary GBM) or develops from a lower grade glioma (secondary GBM). The prognosis is poor. GBMs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12-15 months. One characteristic that is responsible for GBM malignancy, and its worse prognosis, is the highly infiltrative growth of GBM cells into the healthy brain. GBM cell migration and invasion is a very complex process that is regulated by several factors, which include changes in the migrating cell itself as well as the tumor microenvironment. This chapter provides an overview of routes of invasion of glioma cells, the signaling pathways that drive glioma cell motility, and the processes through which glioma cells modulate their surrounding environment.

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Section: Patterns Of Glioma Cell Infiltrationmentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

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“…The FYN shRNA identification numbers are: TRCN0000023383 (shFYN #1) and TRCN0000361213 (shFYN #2). Cells were infected with the lentivirus as described previously by us 15 . Immunoblotting was used to confirm FYN knockdown.…”

Section: Methodsmentioning

confidence: 99%

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

Comba

Dunn

Argento

et al. 2019

Preprint

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BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity.Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

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“…The expression of C-X-C chemokine receptor type 4 (CXCR4) is known to mediate tumor invasion and targeting this receptor has been shown to reduce the invasive properties of GBM cells, sensitizing them towards radiation-induced apoptosis [38]. Importantly, the CXCR4 signaling pathway emerged as one of the most significant biological processes downregulated upon miR-155 overexpression in GBM by DAVID and GSEA analysis ( Fig.…”

Section: Disrupting the Agtr1/nf-κb/cxcr4 Axis Attenuates Oncogenesismentioning

confidence: 99%

Targeting AGTR1/NF-κB /CXCR4 axis by miR-155 attenuates oncogenesis in Glioblastoma

Singh

Srivastava

Ateeq

2019

Preprint

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Glioblastoma (GBM) represents the most aggressive malignancy of the brain. Angiotensin II Receptor Type 1 (AGTR1) upregulation has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3'untranslated region (3'UTR) of AGTR1 by using prediction algorithms for binding of miRNA. Interestingly, miR-155 showed conserved binding on the 3'UTR of AGTR1, subsequently confirmed by AGTR1-3'UTR-luciferase reporter assay. Furthermore, stable miR-155 overexpressing GBM cells show decrease in AGTR1-mediated cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show remarkable reduction (~95%) in tumor burden compared to control. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 and AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated, angiogenesis, epithelial-tomesenchymal transition, stemness, ERK/MAPK signaling and promotes apoptosis. Similar effects in cell-based assays were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies.

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CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study

Cited by 74 publications

References 52 publications

Molecular Mechanisms of Glioma Cell Motility

Molecular Mechanisms of Glioma Cell Motility

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

Targeting AGTR1/NF-κB /CXCR4 axis by miR-155 attenuates oncogenesis in Glioblastoma

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