ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

Unveiling interfacial interaction between antimony oxyanions and boehmite nanorods: Spectroscopic evidence and density functional theory analysis.

In natural environments, the fate and migratory behavior of metalloid contaminants such as antimony (Sb) significantly depend on the interfacial reactivity of mineral surfaces. Although boehmite (γ-AlOOH) is widely observed in (sub)surface environments, its underlying interaction mechanism with Sb oxyanions at the molecular scale remains unclear. Considering Sb-contaminated environmental conditions in this study, we prepared boehmite under weakly acidic conditions for use in the systematic investigation of interfacial interactions with Sb(III) and Sb(V). The as-synthesized boehmite showed a nanorod morphology and comprised four crystal facets in the following order: 48.4% (010), 27.1% (101), 15.0% (001), and 9.5% (100). The combined results of spectroscopic analyses and theoretical calculations revealed that Sb(III) formed hydrogen bonding outer-sphere complexation on the (100), (010), and (001) facets and that Sb(V) preferred to form bidentate inner-sphere complexation via mononuclear edge-sharing configuration on the (100), (001), and (101) facets and binuclear corner-sharing configuration on the (010) facet. These findings indicate that the facet-mediated thermodynamic stability of the surface complexation determines the interaction affinity toward the Sb species. This work is the first to document the contribution of boehmite to (sub)surface media, improving the ability to forecast the fate and behavior of Sb oxyanions at mineral-water interfaces.

Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells.

BACKGROUND: Glioblastoma (GBM) is more difficult to treat than other intractable adult tumors. The main reason that GBM is so difficult to treat is that it is highly infiltrative. Migrasomes are newly discovered membrane structures observed in migrating cells. Thus, they can be generated from GBM cells that have the ability to migrate along the brain parenchyma. However, the function of migrasomes has not yet been elucidated in GBM cells. RESULTS: Here, we describe the composition and function of migrasomes generated along with GBM cell migration. Proteomic analysis revealed that LC3B-positive autophagosomes were abundant in the migrasomes of GBM cells. An increased number of migrasomes was observed following treatment with chloroquine (CQ) or inhibition of the expression of STX17 and SNAP29, which are involved in autophagosome/lysosome fusion. Furthermore, depletion of ITGA5 or TSPAN4 did not relieve endoplasmic reticulum (ER) stress in cells, resulting in cell death. CONCLUSIONS: Taken together, our study suggests that increasing the number of autophagosomes, through inhibition of autophagosome/lysosome fusion, generates migrasomes that have the capacity to alleviate cellular stress.

Synergistic effect in simultaneous removal of cationic and anionic heavy metals by nitrogen heteroatom doped hydrochar from aqueous solutions.

Industrial wastewater typically contains both cationic and anionic heavy metals; therefore, their simultaneous removal must be considered to ensure environmental sustainability. Herein, nitrogen heteroatom (N) doped hydrochar derived from corncob was prepared via facile NH4Cl-aided hydrothermal carbonization and used for the simultaneous adsorption of divalent copper (Cu(II)) and hexavalent chromium (Cr(VI)) in aqueous solutions. During hydrothermal carbonization, NH4Cl played a vital role as the porogen and N dopant, which contributed to the efficient adsorption affinity toward coexisting Cu(II) and Cr(VI). The theoretical maximum adsorption capacities of the N-doped hydrochar were determined to be 1.223 mmol/g for Cu(II) and 1.995 mmol/g for Cr(VI), which were much better than those of the pristine hydrochar. Furthermore, in the binary-component system, the synergistic effect between Cu(II) and Cr(VI) significantly promoted the adsorption affinity of N-doped hydrochar, resulting in adsorption capacities for Cu(II) and Cr(VI) 9.48 and 1.92 times higher than those of the single-component system, respectively. A series of adsorption experiments and spectroscopic analyses demonstrated that multiple mechanisms, including electrostatic shielding, cation bridging, and redox reactions, mutually contributed to the synergistic effect in the adsorption of coexisting Cu(II) and Cr(VI). Overall, the N-doped hydrochar proved to be effective in simultaneously removing both cationic and anionic heavy metal pollutants.

The oncogenic JAG1 intracellular domain is a transcriptional cofactor that acts in concert with DDX17/SMAD3/TGIF2.

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, like formation of the NOTCH1 intracellular domain (NICD1); however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Here we show that JICD1 induces astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to anticancer therapy. The transcriptome, chromatin immunoprecipitation sequencing (ChIP-seq), and proteomics analyses show that JICD1 increases SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. JICD1-driven tumorigenicity is directly regulated by SOX2. Our results demonstrate that, like NICD1, JICD1 acts as a transcriptional cofactor in formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

Cytoplasmic LMO2-LDB1 Complex Activates STAT3 Signaling through Interaction with gp130-JAK in Glioma Stem Cells.

The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus.

Characterization of arsenite (As(III)) and arsenate (As(V)) sorption on synthetic siderite spherules under anoxic conditions: Different sorption behaviors with crystal size and arsenic species.

Arsenite (As(III)) and arsenate (As(V)) uptake by synthesized small- and large-sized siderites (S-siderite and l-siderite) and the effects of crystal size on arsenic sorption were investigated under extremely anoxic and neutral pH conditions. Both siderites exhibited spherical growth mechanism with an inverse relationship between crystal size and specific surface area (SSA). The maximum adsorption capacities normalized to SSA (qm,nor) of S-siderite and l-siderite were 0.161 and 0.174 mg/m2 for As(III), and 1.460 and 0.360 mg/m2 for As(V), respectively, indicating that the sorption affinity of S-siderite depends more on the arsenic species (III and V). Extended X-ray absorption fine structure (EXAFS) revealed that without oxidation change, As(V) adsorbed on both siderites forms inner-sphere complexes through bidentate-binuclear corner-sharing. In contrast, outer-sphere and inner-sphere complexes are formed for As(III) adsorbed on these siderites. In addition, the highest sorption affinity for As(V) uptake by S-siderite is attributed to the precipitation of symplesite (FeII3(AsVO4)2·8H2O), whereas the lowest sorption affinity for As(III) uptake by S-siderite was due to bicarbonates generated by the faster dissolution of S-siderite competing for sorption sites. Our findings suggest that arsenic sorption behaviors and mechanisms are strongly dependent on the arsenic species and the crystal size of siderite.

Retraction fibers produced by fibronectin-integrin α5ß1 interaction promote motility of brain tumor cells.

Glioblastoma (GBM) is a refractory disease that has a highly infiltrative characteristic. Over the past decade, GBM perivascular niche (PVN) has been described as a route of dissemination. Here, we investigated that trailed membrane structures, namely retraction fibers (RFs), are formed by perivascular extracellular matrix (ECM) proteins. By using the anatomical GBM database, we validated that the ECM-related genes were highly expressed in the cells within the PVN where fibronectin (FN) induced RF formation. By disrupting candidates of FN-binding integrins, integrin α5ß1 was identified as the main regulator of RF formation. De novo RFs were produced at the trailing edge, and focal adhesions were actively localized in RFs, indicating that adhesive force makes RFs remain at the bottom surface. Furthermore, we observed that GBM cells more frequently migrated along the residual RFs formed by preceding cells in microfluidic channels in comparison to those in the channels without RFs, suggesting that the infiltrative characteristics GBM could be attributed to RFs formed by the preceding cells in concert with chemoattractant cues. Altogether, we demonstrated that shedding membrane structures of GBM cells are maintained by FN-integrin α5ß1 interaction and promoted their motility .

Enhanced Arsenic (III and V) Removal in Anoxic Environments by Hierarchically Structured Citrate/FeCO3 Nanocomposites.

Novel citrate/FeCO3 nanocomposites (CF-NCs) were synthesized for effective arsenic (III and V) sorption with constant addition of Fe2+ into HCO3- solution in the presence of citrate. This paper is the first report on the formation of CF-NCs, and in this study we investigate the mechanisms of arsenic uptake by the sorbent under anoxic conditions through various solid- and liquid-phase spectroscopic methods, including X-ray absorption spectroscopy. In CF-NCs, citrate was found to be incorporated into the structure of siderite (up to 17.94%) through (Fe2+citrate)- complexes. The crystal morphology of rhombohedral siderite was changed into hierarchically nanostructured spherical aggregates composed of several sheet-like crystals, which improved the surface reactivity in the presence of sufficient citrate. Compared to pure siderite (15.2%), enhanced removal of As(III) in the range of 19.3% to 88.2% was observed, depending on the amount of incorporated citrate. The maximum sorption capacities of CF-NCs for As(III) and As(V) were 188.97 and 290.22 mg/g, respectively, which are much higher than those of previously reported siderite-based adsorbents. It was found that arsenic (III and V) sorption on CF-NCs occurred via bidentate corner-sharing surface complexation, predominantly without changes in the arsenic oxidation states. These results suggest that arsenic (III and V) can be attenuated by siderite in anoxic environments, and this attenuation can be even more effective when siderite is modified by incorporation of organic compounds such as citrate.

Ultrasound-assisted heterogeneous Fenton-like process for bisphenol A removal at neutral pH using hierarchically structured manganese dioxide/biochar nanocomposites as catalysts.

Bisphenol A (BPA) is an important emerging contaminant with endocrine-disrupting potential that has frequently been detected in aquatic environments. In this study, two types of hierarchically structured manganese dioxide/biochar nanocomposites (MnO2/BCs) were prepared for the first time via facile hydrothermal synthesis. The hydrothermal reaction was maintained at 100 °C for 6 h or 12 h, after which an ultrasound-assisted heterogeneous Fenton-like process was used to catalyze the removal of BPA under neutral pH condition. The characterization results indicated that MnO2 nanoparticles were successfully formed on the nanocomposite surfaces and had flower-like (δ-MnO2, 6 h) and urchin-like (α-MnO2, 12 h) morphology. This enabled a significant improvement in the catalytic activity of BPA removal by the reversible redox reaction. A series of experiments confirmed that the crystalline properties of the nanocomposites affected their catalytic activity. In particular, the α-MnO2/BCs exhibited catalytic activity in the ultrasound-assisted heterogeneous Fenton-like process and completely removed BPA within 20 min under the following conditions: [BPA]0 = 100 µM; [H2O2]0 = 10 mM; [catalyst]0 = 0.5 g/L; ultrasound = 20 kHz (130 W) at 40% amplitude; pH = 7.0 ±â€¯0.1; and temperature = 25 ±â€¯1 °C. This efficiency may have been due to the synergistic effect of ultrasound and α-MnO2/BCs, which simultaneously induce the effective generation of reactive free radicals and increase the mass transfer rate at the solid-liquid interface. Overall, these results demonstrated that hierarchical urchin-like α-MnO2/BCs have significant potential as an efficient and low-cost catalyst in ultrasound-assisted heterogeneous Fenton-like systems.

Korean Red ginseng extract inhibits glioblastoma propagation by blocking the Wnt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean Red ginseng extract (RG) is one of the most widely used traditional health functional food in Asia, which invigorates immunity and vital energy. RG have been suggested to inhibit proliferation, invasion, and inflammation in several cancer cell lines. Correspondingly, clinical studies have raised the possibility that RG could augment therapeutic efficacy in cancer patients. However, little is known about the anti-cancer effects of RG in glioblastoma (GBM), the most common and aggressive brain tumor for which effective therapeutic regimens need to be developed. AIM OF THIS STUDY: Here, we assessed the in vivo and in vitro anti-cancer properties of RG in a patient-derived xenograft mouse model and GBM stem cell (GSC) line. MATERIALS AND METHODS: We evaluated the anti-cancer effects of RG in patient-derived GBM xenograft mice with and without combined concurrent chemo- and radiation therapy (CCRT). Furthermore, we verified the in vitro effects of RG on the proliferation, cell death, and stem cell-like self-renewal capacity of cancer cells. Finally, we investigated the signaling pathway affected by RG, via which its anti-cancer effects were mediated. RESULTS: When combined with CCRT, RG impeded GBM progression by reducing cancer cell proliferation and ionized calcium-binding adapter molecule 1 (IBA1)-positive immune cell recruitment. The anti-cancer effects of RG were mediated by Rg3 and Rh2 ginsenosides. Rg3 promoted cell death while Rh2 did not. Furthermore, both Rg3 and Rh2 reduced cell viability and self-renewal capacity of GSCs by inhibiting Wnt/ß-catenin signaling. CONCLUSION: Therefore, our observations imply that RG could be applied to the GBM patients in parallel with CCRT to enhance therapeutic efficacy.

Ly6G+ inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.

Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.

TP53 gain-of-function mutation promotes inflammation in glioblastoma.

Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.

Facile one-pot hydrothermal synthesis of cubic spinel-type manganese ferrite/biochar composites for environmental remediation of heavy metals from aqueous solutions.

This study reports the facile synthesis of cubic spinel-type manganese ferrite (MnFe2O4)/biochar (MF/BC) composites via a one-pot hydrothermal technique. Multiple characterizations demonstrated that the MnFe2O4 spinel nanoparticles were successfully grown on the biochar, which provides magnetic separability with superparamagnetic behavior and effective adsorption performance for heavy metals (Pb(II), Cu(II), and Cd(II)). The adsorption kinetics and isotherms can be well described with a pseudo-second-order and Sips isotherm models, respectively. Comparative adsorption in multi-heavy metal systems (binary and ternary) indicated that the adsorption affinity of MF/BC composites toward heavy metals followed the sequence of Pb(II) > Cu(II) > Cd(II), which followed the order of their covalent indexes. Thermodynamic analysis revealed that the adsorption process was endothermic and primarily governed by physisorption. This study provides a feasible and simple approach for the preparation of high-performance materials for the remediation of heavy metal-contaminated wastewater in a cost-effective manner.

Hydrothermal synthesis of hierarchically structured birnessite-type MnO2/biochar composites for the adsorptive removal of Cu(II) from aqueous media.

In this study, hierarchical birnessite-type MnO2/biochar composites (δ-MnO2/BCs) were synthesized by a hydrothermal technique, and their Cu(II) removal performance was examined in aqueous solution. Morphological characterization confirmed that a three-dimensional flower-like structure of δ-MnO2 was formed, which results in effective adsorption affinity towards Cu(II). The effects of solution pH, adsorbent dosage, and ionic strength on the adsorption behavior of the prepared materials were systemically investigated. The adsorption kinetics indicated that Cu(II) adsorption onto δ-MnO2/BCs follows a pseudo-second-order model. Analysis of possible adsorption/diffusion mechanisms suggested that the adsorption process is controlled by both film and pore diffusion. The adsorption isotherms fit closely to the Sips isotherm model, and the theoretical maximum adsorption capacities of Cu(II) on the synthesized δ-MnO2/BCs are approximately 124, 154, 199, and 230 mg/g at 15, 25, 35, and 45 °C, respectively. Adsorption-desorption studies demonstrated the recyclability of the δ-MnO2/BCs for the removal of Cu(II) from aqueous solutions.

Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy.

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383-94. ©2017 AACR.

SV40 Large T Antigen Disrupts Embryogenesis of Canine and Porcine Somatic Cell Nuclear Transfer Embryo.

BACKGROUND: Somatic cell nuclear transfer (SCNT) is a useful biotechnological tool for transgenic animal production using genetically modified somatic cells (GMSCs). However, there are several limitations preventing successful transgenic animal generation by SCNT, such as obtaining proper somatic donor cells with a sufficiently long life span and proliferative capacity for generating GMSCs. Here, we established simian virus 40 large T antigen (SV40LT)-mediated lifespan-extended canine fibroblast cells (SV40LT-K9 cells) and evaluated their potential as nuclei donors for SCNT, based on cellular integrity and SCNT embryo development. RESULTS: SV40LT did not cause canine cell transformation, based on cell morphology and proliferation rate. No anchorage-independent growth in vitro and tumorigenicity in vivo were observed. After SCNT with SV40LT-K9 cells, embryos were transferred into surrogate dogs. All dogs failed to become pregnant. Most embryos did not proceed past the 8-cell stage and only one surrogate showed an implantation trace in its oviduct, indicating that the cells rarely developed into blastocysts. Because of the absence of an in vitro maturation method for canine embryos, we performed identical experiments using porcine fibroblast cells. Similarly, SV40LT did not transform porcine fibroblast cells (SV40LT-Pig cells). During in vitro development of SV40LT-Pig cell-driven SCNT embryos, their blastocyst formation rate was clearly lower than those of normal cells. Karyotyping analysis revealed that both SV40LT-K9 and SV40LT-Pig cells had aberrant chromosomal statuses. CONCLUSIONS: Although lifespan-extended canine and porcine cells via SV40LT exhibit no apparent transforming changes, they are inappropriate for use as nuclei donors for SCNT because of their aneuploidy.

BRM270, a Compound from Natural Plant Extracts, Inhibits Glioblastoma Stem Cell Properties and Glioblastoma Recurrence.

Glioblastoma multiforme (GBM) is one of the most aggressive and lethal human brain tumors, and the median survival of patients with GBM is only 14 months. Glioblastoma stem cells (GSCs) are regarded as a main cause of GBM recurrence, because of their self-renewal and drug resistance properties. Therefore, targeting GSCs is an important therapeutic strategy for GBM. In this study, we show the effects of BRM270, a compound from natural plant extracts, on GSCs in vitro and GBM recurrence in vivo. BRM270 induced apoptotic cell death and inhibited cell growth and "stemness" both in vitro and in vivo. Combining BRM270 treatment with concurrent chemoradiotherapy (CCRT) dramatically increased mice survival and tumor growth inhibition. Taken together, our results suggested that BRM270 synergizes with CCRT as a therapeutic agent to target GSCs.

CD133 Regulates IL-1ß Signaling and Neutrophil Recruitment in Glioblastoma.

CD133, a pentaspan transmembrane glycoprotein, is generally used as a cancer stem cell marker in various human malignancies, but its biological function in cancer cells, especially in glioma cells, is largely unknown. Here, we demonstrated that forced expression of CD133 increases the expression of IL-1ß and its downstream chemokines, namely, CCL3, CXCL3 and CXCL5, in U87MG glioma cells. Although there were no apparent changes in cell growth and sphere formation in vitro and tumor growth in vivo, in vitro trans-well studies and in vivo tumor xenograft assays showed that neutrophil recruitment was markedly increased by the ectopic expression of CD133. In addition, the clinical relevance between CD133 expression and IL-1ß gene signature was established in patients with malignant gliomas. Thus, these results imply that glioma cells expressing CD133 are capable of modulating tumor microenvironment through the IL-1ß signaling pathway.

A cell-autonomous positive-signaling circuit associated with the PDGF-NO-ID4-regulatory axis in glioblastoma cells.

Most cancer-related signaling pathways sustain their active or inactive status via genetic mutations or various regulatory mechanisms. Previously, we demonstrated that platelet-derived growth factor (PDGF) activates Notch signaling through nitric oxide (NO)-signaling-driven activation of inhibitor of differentiation 4 (ID4) in glioblastoma (GBM) stem cells (GSCs) and endothelial cells in the vascular niche of GBM, leading to maintenance of GSC traits and GBM progression. Here, we determined that the PDGF-NO-ID4-signaling axis is constantly activated through a positive regulatory circuit. ID4 expression significantly increased PDGF subunit B expression in both in vitro cultures and in vivo tumor xenografts and regulated NO synthase 2 (NOS2) expression and NO production by activating PDGF signaling, as well as that of its receptor (PDGFR). Additionally, ectopic expression of PDGFRα, NOS2, or ID4 activated the PDGF-NO-ID4-signaling circuit and enhanced the self-renewal of GBM cell lines. These results suggested that the positive regulatory circuit associated with PDGF-NO-ID4 signaling plays a pivotal role in regulating the self-renewal and tumor-initiating capacity of GSCs and might provide a promising therapeutic target for GBM.