Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma

Ahir, Bhavesh K.; Engelhard, Herbert H.; Lakka, Sajani S.

doi:10.1007/s12035-020-01892-8

Cited by 296 publications

(246 citation statements)

References 180 publications

(169 reference statements)

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“…Differential effects mediated by β adrenergic agonists, and the congruent effects paradoxically mediated by pharmacological antagonists of β adrenergic receptor modulated signaling, upon non-malignantly transformed and glioma cellular proliferation may result from differential activation of downstream intracellular signal transduction pathways promoted by agonist ligand binding to, and/or desensitization of βAR and phospho-βAR-β arrestin scaffold assembly [6,72,[76][77][78][79][80]. Stimulation of βAR stimulates the AC-cAMP-PKA-ERK1/2 pathway, effectively promoting cellular proliferation [81].…”

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

“…Cerebral, brainstem, and cerebellar gliomas exhibit heterogeneous arteriolar density [112]. Tumor neoangiogenesis promotes glioma growth, promotion, progression, invasion, and metastasis of gliomas [6,76] and extra-neuraxial [113,114] carcinomas, subject to modulation by β adrenergic receptor modulated signaling. Treatment with norepinephrine [115] or dopamine [116] and stress promote angiogenesis in ovarian carcinomas by potentiating βAR mediated attenuation of PPARγ signaling and thus disinhibiting the synthesis of VEGF and FGF2, molecular behavior putatively extending to cerebral gliomas [116].…”

Section: Modulation Of Angiogenesis By β Adrenergic Signalingmentioning

confidence: 99%

“…To this end, pediatricians now commonly espouse the use of propranolol to effect involution of the vascular endothelium in infants harboring benign hemangiomas [6]. The revealed set of molecular effects may be exploited to therapeutic benefit to generate marked reductions in glioma [6,76] and extra-neuraxial [113,114] hypervascular carcinoma growth potential, invasiveness, and angiogenesis. The effects of antiangiogenic compounds are characteristically amplified in the presence of ionizing radiation [117].…”

Section: Modulation Of Angiogenesis By β Adrenergic Signalingmentioning

confidence: 99%

“…Multimodal strategies seeking to optimize the development of compounds promoting stable GPCR-β arrestin interactions and contemporaneous treatment with specific ERK inhibitors may maximize the actualized survival benefit in patients harboring gliomas and extra-neuraxial malignancy [9,14,111]. These therapies may prove of clinical utility in curtailing initiation, promotion, and progression of gliomas and may prove to represent a useful general adjuvant to multimodal therapy of glioblastoma [6,76,111]. Immunomodulatory effects of β adrenergic signaling, prominently regulating cell surface expression of MHC class II, suggests manipulating these pathways may represent an effective adjuvant technique to be utilized in conjunction with various immunotherapeutic approaches, including generation of tumor specific antibodies, cytotoxic T cells, and NK cells in a variety of cancers [124].[N.B.…”

Section: Drug Developmentmentioning

confidence: 99%

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RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

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Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

Section: Modulation Of Angiogenesis By β Adrenergic Signalingmentioning

confidence: 99%

Section: Modulation Of Angiogenesis By β Adrenergic Signalingmentioning

confidence: 99%

Section: Drug Developmentmentioning

confidence: 99%

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RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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“…The transverse relaxation time of blood water protons depends to some extent on the surrounding tissue properties and also on the blood oxygenation level. Likewise, the tissue characteristics and vascularization change in tumors, thereby impacting the blood oxygenation status and tissue perfusion 25 , 26 . It may be presumed that the -weighted ASL signal will be also altered and therefore , combined with the perfusion parameters CBF and ATT, might provide a non-invasive basis for a comprehensive model for disease characterization.…”

Section: Discussionmentioning

confidence: 99%

Reliability of quantitative transverse relaxation time mapping with $${\text{T}}_{{2}}$$-prepared whole brain pCASL

Schidlowski

Stirnberg

Stöcker

et al. 2020

Sci Rep

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Arterial spin labeling (ASL) is increasingly applied for cerebral blood flow mapping, but $${\text{T}}_{{2}}$$ T 2 relaxation of the ASL signal magnetization is often ignored, although it may be clinically relevant. To investigate the extent, to which quantitative $${\text{T}}_{{2}}$$ T 2 values in gray matter (GM) obtained by pseudocontinuous ASL (pCASL) perfusion MRI can be reproduced, are reliable and a potential neuroscientific biomarker, a prospective study was performed with ten healthy volunteers (5F,28 ± 3y) at a 3 T scanner. A $${\text{T}}_{{2}}$$ T 2 -prepared pCASL sequence enabled the measurement of quantitative $${\text{T}}_{{2}}$$ T 2 and perfusion maps. $${\text{T}}_{{2}}$$ T 2 times were modeled per voxel and analyzed within four GM-regions-of-interest (ROI). The intraclass correlation coefficients (ICCs) of the quantified ASL-$${\text{T}}_{{2}}$$ T 2 varied across brain regions. When averaged across subjects and postlabeling delays (PLDs), the ICCs ranged from reasonable values in parietal regions (ICC = 0.56) to smaller values in frontal regions (ICC = 0.36). Corresponding subject-averaged within-subject coefficients of variation (WSCVs) showed good test–retest measurement precision ($${\text{WSCV}}_{{{\text{PLD}}}} \le 0.14$$ WSCV PLD ≤ 0.14 for all PLDs), but more pronounced inter-subject variance. Reliability and precision of quantified ASL-$${\text{T}}_{{2}}$$ T 2 were region-, PLD- and subject-specific, showing fair to robust results in occipital, parietal and temporal ROIs. The results give rise to consider the method for future cerebral studies, where variable perfusion or altered $${\text{T}}_{{2}}$$ T 2 times are suspected.

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Development of an optimized, non‐stem cell line for intranasal delivery of therapeutic cargo to the central nervous system

El‐Ayoubi,

Arakelyan,

Klawitter

et al. 2023

Molecular Oncology

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Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti‐cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX‐2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non‐tumorigenic after INA. Our data show that LX‐2 cells can longer withstand the OAV XVir‐N‐31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX‐2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV‐TK) integration into LX‐2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno‐compromised mice 3 months after INA of LX‐2 cells. Our data suggest that LX‐2 is a novel, robust, and safe cell line for delivering anti‐cancer and other therapeutic agents to the brain.

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Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma

Cited by 296 publications

References 180 publications

Reliability of quantitative transverse relaxation time mapping with $${\text{T}}_{{2}}$$-prepared whole brain pCASL

Development of an optimized, non‐stem cell line for intranasal delivery of therapeutic cargo to the central nervous system

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