bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒09‒19
seventeen papers selected by
Oltea Sampetrean
Keio University

  1. Mol Cancer Res. 2021 Sep 14. pii: molcanres.MCR-19-0995-E.2019. [Epub ahead of print]
      The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma (GBM). Poor drug entry across the BTB allows infiltrative glioma stem cells (GSC) to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier (BBB) in non-tumor bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, down-regulation of junctional protein expression by 4 hours, and re-establishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide (TMZ) concentrations, yet no increased survival noted with combined TMZ therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes amongst glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance CNS treatment delivery to aggressive brain tumors. Implications: This study provides insight on the use of a vasoactive agent to increase exposure of the blood-tumor barrier to chemotherapy with intention to improve glioma treatment efficacy.
  2. Cell Rep. 2021 Sep 14. pii: S2211-1247(21)01167-0. [Epub ahead of print]36(11): 109718
      Scant understanding of the glioblastoma microenvironment and molecular bases hampers development of efficient treatment strategies. Analyses of gene signatures of human gliomas demonstrate that the SETD2 mutation is correlated with poor prognosis of IDH1/2 wild-type (IDH-WT) adult glioblastoma patients. To better understand the crosstalk between SETD2 mutant (SETD2-mut) glioblastoma cells and the tumor microenvironment, we leverage single-cell transcriptomics to comprehensively map cellular populations in glioblastoma. In this study, we identify a specific subtype of high-grade glioma-associated microglia (HGG-AM). Further analysis shows that transforming growth factor (TGF)-β1 derived from SETD2-mut/IDH-WT tumor cells activates HGG-AM, exhibiting pro-inflammation and proliferation signatures. Particularly, HGG-AM secretes interleukin (IL)-1β via the apolipoprotein E (ApoE)-mediated NLRP1 inflammasome, thereby promoting tumor progression. HGG-AM present extensive proliferation and infiltration to supplement the activated microglia pool. Notably, TGF-β1/TβRI depletion dramatically reduces HGG-AM density and suppresses tumor growth. Altogether, our studies identify a specific microglia subpopulation and establish the cellular basis of interactions between HGG-AM and glioblastoma cells.
  3. Am J Cancer Res. 2021 ;11(8): 3742-3754
      Extracellular matrix is a complex network of macromolecules that constitute a microenvironment of normal tissues and malignancies such as the primary brain tumor glioblastoma (GBM). The unique composition of the GBM ECM, compared with the brain, contributes to angiogenesis, invasion, and therapeutic resistance of GBM. On the other hand, components of tumor ECM and related aberrant signaling pathways offer opportunities for various therapeutic strategies that are under active investigations. Here we provide a comprehensive overview of emerging therapeutic approaches for GBM that target or utilize its unique ECM via antibodies or ligands, RNA interference, pharmacological agents and modification of ECM molecules. Furthermore, drug-loaded nanoparticles displaying ECM-directed antibodies or peptides enable tumor selective delivery of the payload. As an in vitro research platform, 3D tumor cell culture incorporating ECM can advance our understanding of tumor-ECM interactions.
    Keywords:  3D culture; Extracellular matrix; antibodies; chemotherapy; glioblastoma; nanoparticles; oncolytic viruses; peptides; tumor microenvironment
  4. Nanomedicine (Lond). 2021 Sep 15.
      Aim: To develop and characterize bozepinib-loaded lipid-core nanocapsules (BZP-LNC+) as a potential treatment for glioblastoma (GBM). Methods: Characterization of nanocapsules was performed by diameter, polydispersity index, zeta potential, pH and encapsulation efficiency. GBM cell viability, cell cycle and Annexin/PI were evaluated after BZP-LNC+ treatment. Synergism between BZP-LNC+ and temozolomide (TMZ) was performed by CompuSyn software and confirmed in vitro and in vivo. Results: BZP-LNC+ showed adequate particle sizes, positive zeta potential, narrow size distribution and high encapsulation efficiency. BZP-LNC+ reduces GBM growth by inducing apoptosis. BZP-LNC+ and TMZ showed synergistic effect in vitro and reduced the in vivo glioma growth by approximately 81%. Conclusion: The present study provides proof-of-principle insights for the combination of these drugs for GBM treatment.
    Keywords:  bozepinib; drug delivery; glioblastoma; intranasal; lipid-core nanocapsules; temozolomide
  5. Mol Syst Biol. 2021 Sep;17(9): e10105
      Tumor cell heterogeneity is a crucial characteristic of malignant brain tumors and underpins phenomena such as therapy resistance and tumor recurrence. Advances in single-cell analysis have enabled the delineation of distinct cellular states of brain tumor cells, but the time-dependent changes in such states remain poorly understood. Here, we construct quantitative models of the time-dependent transcriptional variation of patient-derived glioblastoma (GBM) cells. We build the models by sampling and profiling barcoded GBM cells and their progeny over the course of 3 weeks and by fitting a mathematical model to estimate changes in GBM cell states and their growth rates. Our model suggests a hierarchical yet plastic organization of GBM, where the rates and patterns of cell state switching are partly patient-specific. Therapeutic interventions produce complex dynamic effects, including inhibition of specific states and altered differentiation. Our method provides a general strategy to uncover time-dependent changes in cancer cells and offers a way to evaluate and predict how therapy affects cell state composition.
    Keywords:  cell state; cellular barcoding; patient-derived brain tumor cells; single-cell lineage tracing; time-dependent computational models
  6. Cancer Metastasis Rev. 2021 Sep 14.
      Glioblastoma multiforme (GBM) is the most invasive type of glial tumor with poor overall survival, despite advances in surgical resection, chemotherapy, and radiation. One of the main challenges in treating GBM is related to the tumor's location, complex and heterogeneous biology, and high invasiveness. To meet the demand for oxygen and nutrients, growing tumors induce new blood vessels growth. Antibodies directed against vascular endothelial growth factor (VEGF), which promotes angiogenesis, have been developed to limit tumor growth. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, is the first approved angiogenesis inhibitor with therapeutic promise. However, it has limited efficacy, likely due to adaptive mutations in GBM, leading to overall survival compared to the standard of care in GBM patients. Molecular connections between angiogenesis, inflammation, oxidative stress pathways, and the development of gliomas have been recognized. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the converging dysregulation of signaling pathways. While most GBM clinical trials focus on "anti-angiogenic" modalities, stimulating inflammation resolution is a novel host-centric therapeutic avenue. The selective therapeutic possibilities for targeting the tumor microenvironment, specifically angiogenic and inflammatory pathways expand. So, a combination of agents aiming to interfere with several mechanisms might be beneficial to improve outcomes. Our approach might also be combined with other therapies to enhance sustained effectiveness. Here, we discuss Suramab (anti-angiogenic), LAU-0901 (a platelet-activating factor receptor antagonist), Elovanoid (ELV; a novel lipid mediator), and their combination as potential alternatives to contain GBM growth and invasiveness.
    Keywords:  Glioma; Lipid mediators; Oncology; Platelet-activating factor; Suramin
  7. EBioMedicine. 2021 Sep 13. pii: S2352-3964(21)00364-9. [Epub ahead of print]71 103571
      BACKGROUND: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment.METHODS: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT.
    FINDINGS: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy.
    INTERPRETATION: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses.
    FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
    Keywords:  Theranostics; bifunctional chelator; checkpoint immunotherapy; gliomas; immunoPET; targeted radiotherapy
  8. Front Oncol. 2021 ;11 743814
      Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.
    Keywords:  cancer metabolism; cancer stem cell (CSC); glioma stem-like cell; metabolic reprogramming; therapeutic strategies
  9. J Proteome Res. 2021 Sep 17.
      Medulloblastomas (MBs) and glioblastomas (GBMs) are high-incidence central nervous system tumors. Different origin sites and changes in the tissue microenvironment have been associated with the onset and progression. Here, we describe differences between the extracellular matrix (ECM) signatures of these tumors. We compared the proteomic profiles of MB and GBM decellularized tumor samples between each other and their normal decellularized brain site counterparts. Our analysis revealed that 19, 28, and 11 ECM proteins were differentially expressed in MBs, GBMs, and in both MBs and GBMs, respectively. Next, we validated key findings by using a protein tissue array with 53 MB and 55 GBM cases and evaluated the clinical relevance of the identified differentially expressed proteins through their analysis on publicly available datasets, 763 MB samples from the GSE50161 and GSE85217 studies, and 115 GBM samples from RNAseq-TCGA. We report a shift toward a denser fibrillary ECM as well as a clear alteration in the glycoprotein signature, which influences the tumor pathophysiology. MS data have been submitted to the PRIDE repository, project accession: PXD023350.
    Keywords:  decellularization; extracellular matrix; glioblastoma; mass spectrometry; medulloblastoma; proteome
  10. BMC Cancer. 2021 Sep 15. 21(1): 1025
      BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas.METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis.
    RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology.
    CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.
    Keywords:  Astrocytoma; Ganglioglioma; Glioma; Histological phenotype; Oligodendroglioma; RAS mutation
  11. Biomed Pharmacother. 2021 Sep 09. pii: S0753-3322(21)00928-8. [Epub ahead of print]143 112144
      Glioblastoma multiforme (GBM) is a grade IV malignant brain tumor with a median survival time of approximately 12-16 months. Because of its highly aggressive and heterogeneous nature it is very difficult to remove by surgical resection. Herein we have reported dual stimuli-responsive and biodegradable in situ hydrogels of oligosulfamethazine-grafted gelatin and loaded with anticancer drug paclitaxel (PTX) for preventing the progress of Glioblastoma. The oligosulfamethazine (OSM) introduced to the gelatin backbone for the formation of definite and stable in situ hydrogel. The hydrogels transformed from a sol to a gel state upon changes in stimuli. pH and temperature and retained a distinct shape after subcutaneous administration in BALB/c mice. The viscosity of the sol state hydrogels was tuned by varying the feed molar ratio between gelatin and OSM. The porosity of the hydrogels was confirmed to be lower in higher degree OSM by SEM. Sustained release of PTX from hydrogels in physiological environments (pH 7.4) was further retarded up to 63% in 9th days in tumor environments (pH 6.5). While the empty hydrogels were non-toxic in cultured cells, the hydrogels loaded with PTX showed antitumor efficacy in orthotopic-GBM xenograft mice. Collectively, the gelatin-OSM formed porous hydrogels and released the cargo in a sustained manner in tumor environments efficiently suppressing the progress of GBM. Thus, gelatin-OSM hydrogels are a potential candidate for the direct delivery of therapeutics to the local areas in brain diseases.
    Keywords:  Drug delivery systems; Gelatin; Glioblastoma multiforme (GBM); Paclitaxel; Stimuli responsive
  12. Autophagy. 2021 Sep 17. 1-23
      Cancer cell growth is dependent upon the sustainability of proliferative signaling and resisting cell death. Macroautophagy/autophagy promotes cancer cell growth by providing nutrients to cells and preventing cell death. This is in contrast to autophagy promoting cell death under some conditions. The mechanism regulating autophagy-mediated cancer cell growth remains unclear. Herein, we demonstrate that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor that suppresses cancer cell growth and tumor growth and prevents cell death induction during excessive growth by inhibiting autophagy. The oncogenic proteins ERBB2 (erb-b2 receptor tyrosine kinase 2) and the activation EGFR mutant (EGFRvIII, epidermal growth factor receptor variant III) promote cell growth and TSSC4 expression in breast cancer and glioblastoma multiforme (GBM) cells, respectively. In EGFRvIII-expressing GBM cells, TSSC4 knockout shifted the function of autophagy from a pro-cell survival role to a pro-cell death role during prolonged cell growth. Furthermore, the interaction of TSSC4 with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via its conserved LC3-interacting region (LIR) contributes to its inhibition of autophagy. Finally, TSSC4 suppresses tumorsphere formation and tumor growth by inhibiting autophagy and maintaining cell survival in tumorspheres. Taken together, sustainable cancer cell growth can be achieved by autophagy inhibition via TSSC4 expression.ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; CQ: chloroquine; EGFRvIII: epidermal growth factor receptor variant III; ERBB2: erb-b2 receptor tyrosine kinase 2; GBM: glioblastoma multiforme; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule Associated protein 1 light chain 3; TSSC4: tumor suppressing subtransferable candidate 4.
    Keywords:  Autophagic cell death; EGFR; ERBB2; cell growth; tumorsphere
  13. Front Oncol. 2021 ;11 692650
      Glioblastoma progression involves multifaceted changes in vascularity, cellularity, and metabolism. Capturing such complexities of the tumor niche, from the tumor core to the periphery, by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods has translational impact. In human-derived glioblastoma models (U87, U251) we made simultaneous and longitudinal measurements of tumor perfusion (Fp), permeability (Ktrans), and volume fractions of extracellular (ve) and blood (vp) spaces from dynamic contrast enhanced (DCE) MRI, cellularity from apparent diffusion coefficient (ADC) MRI, and extracellular pH (pHe) from an MRSI method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Spatiotemporal patterns of these parameters during tumorigenesis were unique for each tumor. While U87 tumors grew faster, Fp, Ktrans, and vp increased with tumor growth in both tumors but these trends were more pronounced for U251 tumors. Perfused regions between tumor periphery and core with U87 tumors exhibited higher Fp, but Ktrans of U251 tumors remained lowest at the tumor margin, suggesting primitive vascularization. Tumor growth was uncorrelated with ve, ADC, and pHe. U87 tumors showed correlated regions of reduced ve and lower ADC (higher cellularity), suggesting ongoing proliferation. U251 tumors revealed that the tumor core had higher ve and elevated ADC (lower cellularity), suggesting necrosis development. The entire tumor was uniformly acidic (pHe 6.1-6.8) early and throughout progression, but U251 tumors were more acidic, suggesting lower aerobic glycolysis in U87 tumors. Characterizing these cancer hallmarks with DCE-MRI, ADC-MRI, and BIRDS-MRSI will be useful for exploring tumorigenesis as well as timely therapies targeted to specific vascular and metabolic aspects of the tumor microenvironment.
    Keywords:  MRI; cellularity; chemical shift imaging; dynamic contrast enhanced imaging; extracellular pH; glioblastoma; tumor microenvironment; vascularity
  14. Int J Radiat Oncol Biol Phys. 2021 Sep 14. pii: S0360-3016(21)02816-9. [Epub ahead of print]
      PURPOSE: Infiltrative growth pattern is a hallmark of glioblastoma (GBM). Radiotherapy aims to eradicate microscopic residual GBM cells post-surgical removal of the visible tumor bulk. However, in field recurrences remain the major pattern of therapy failure. We hypothesized that the radiosensitivity of peripheral invasive tumor cells (peri) may differ from predominantly investigated tumor bulk.MATERIAL AND METHODS: Invasive GBM populations were generated via debulking of the visible tumor core and serial orthotopic transplantation of peri cells and sustained pro-invasive phenotype of peri cell was confirmed in-vitro by scratch assay and time lapse imaging. In parallel, invasive GBM cells were selected by transwell assay and from peri cells of patient derived 3D spheroid cultures. Transcriptome analysis deciphered a GBM invasion associated gene signature and functional involvement of key pathways was validated by pharmacological inhibition.
    RESULTS: Compared to the bulk cells, invasive GBM populations acquired a radioresistant phenotype characterized by increased cell survival, reduced cell apoptosis and enhanced DNA double strand break (DSB) repair proficiency. Transcriptome analysis revealed a reprograming of invasive cells towards augmented activation of EGFR and NF-κB related pathways while metabolic processes were downregulated. An invasive GBM score (iGS) derived from this transcriptional fingerprint correlated well with patient outcome. Inhibition of EGFR and NF-κB signaling re-sensitized invasive cells to irradiation. Invasive cells were eradicated with similar efficacy by particle therapy with carbon ions.
    CONCLUSIONS: Our data indicate that invasive tumor cells constitute a phenotypically distinct and highly radioresistant GBM subpopulation with prognostic impact that may be vulnerable to targeted therapy and carbon-ions.
    Keywords:  EGFR, NF-κB; GBM; carbon-ions; invasion; radioresistance