bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2020‒07‒26
fifteen papers selected by
Oltea Sampetrean
Keio University


  1. Am J Pathol. 2020 Jul 18. pii: S0002-9440(20)30339-4. [Epub ahead of print]
    Ding Z, Dong Z, Yang Y, Fortin Ensign SP, Sabit H, Nakada M, Ruggieri R, Kloss JM, Symons M, Tran NL, Loftus JC.
      Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. A hallmark of GBM is aggressive invasion of tumor cells into the surrounding normal brain. The current standard of care therapy, as well as targeted therapies, have largely failed to specifically address this issue. Therefore, identifying key regulators of GBM cell migration and invasion is of particular interest. The leukemia-associated RhoGEF (LARG) has previously been implicated in cell invasion in other tumor types; however, the role of LARG in GBM pathobiology remains undefined. Here, we report that the expression level of LARG, RhoC, and RhoA increases with glial tumor grade and is highest in GBM. LARG and RhoC protein expression is more prominent in the invading cells whereas RhoA expression is largely restricted to cells in the tumor core. Knockdown of LARG by siRNA inhibits GBM cell migration in vitro and invasion ex vivo in organotypic brain slices. Moreover, siRNA mediated silencing of RhoC suppresses GBM cell migration in vitro and invasion ex vivo, whereas depletion of RhoA enhances GBM cell migration and invasion, supporting a role for LARG and RhoC in GBM cell migration and invasion. Depletion of LARG increases the sensitivity of GBM cells to temozolomide treatment. Collectively, these results suggest that LARG and RhoC may represent unappreciated targets to inhibit glioma invasion.
    Keywords:  LARG; RhoA; RhoC; RhoGEF; cell invasion; glioblastoma
    DOI:  https://doi.org/10.1016/j.ajpath.2020.07.005
  2. Pharmaceuticals (Basel). 2020 Jul 19. pii: E156. [Epub ahead of print]13(7):
    Escamilla-Ramírez A, Castillo-Rodríguez RA, Zavala-Vega S, Jimenez-Farfan D, Anaya-Rubio I, Briseño E, Palencia G, Guevara P, Cruz-Salgado A, Sotelo J, Trejo-Solís C.
      Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.
    Keywords:  autophagy; chemotherapy; glioma
    DOI:  https://doi.org/10.3390/ph13070156
  3. Cancers (Basel). 2020 Jul 19. pii: E1960. [Epub ahead of print]12(7):
    Miyazaki T, Ishikawa E, Sugii N, Matsuda M.
      Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells-including M2-type macrophages and myeloid-derived suppressor cells-that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.
    Keywords:  M2-type macrophages; glioma; immune-checkpoint molecules; immunosuppressive tumor microenvironment; tumor vaccine
    DOI:  https://doi.org/10.3390/cancers12071960
  4. Int J Mol Sci. 2020 Jul 20. pii: E5113. [Epub ahead of print]21(14):
    Kerstetter-Fogle AE, Harris PLR, Brady-Kalnay SM, Sloan AE.
      Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model. Furthermore, the high passage number of cultured cells and clonal selection fail to recapitulate the molecular and genomic signatures of GBM. We have established orthotopic patient-derived xenografts (PDX) from 37 GBM patients with human GBM. Of the 69 patient samples analyzed, we were successful in passaging 37 lines three or more generations (53.6%). After phenotypic characterization of the xenografted tumor tissue, two different growth patterns emerged highly invasive or localized. The phenotype was dependent on malignancy and previous treatment of the patient from which the xenograft was derived. Physiologically, mice exhibited symptoms more quickly with each subsequent passage, particularly in the localized tumors. Study of these physiologically relevant human xenografts in mice will enable therapeutic screenings in a microenvironment that more closely resembles GBM and may allow development of individualized patient models which may eventually be used for simulating treatment.
    Keywords:  GBM; intracranial; patient-derived xenograft; preclinical
    DOI:  https://doi.org/10.3390/ijms21145113
  5. Cancers (Basel). 2020 Jul 19. pii: E1964. [Epub ahead of print]12(7):
    Balakrishnan A, Roy S, Fleming T, Leong HS, Schuurmans C.
      Gliomas are a diverse group of brain tumors comprised of malignant cells ('tumor' cells) and non-malignant 'normal' cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both 'tumor' and 'normal' cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell-cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that 'vesiculome' data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.
    Keywords:  biomarkers; extracellular vesicles; glioma; liquid biopsy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers12071964
  6. Cancer Cell Int. 2020 ;20 310
    Chen X, Guo ZQ, Cao D, Chen Y, Chen J.
      Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. DEPDC1B (DEP domain-containing protein 1B) has been shown to be associated with some types of malignancies. However, the role and underlying regulatory mechanisms of DEPDC1B in GBM remain elusive.Methods: In this research, the expression level of DEPDC1B in GBM tissues was detected by IHC. The DEPDC1B knockdown cell line was constructed, identified by qRT-PCR and western blot and used to construct the xenotransplantation mice model and intracranial xenograft model. MTT assay, colony formation assay, flow cytometry, and Transwell assay were used to detected cell proliferation, apoptosis and migration.
    Results: The results proved that DEPDC1B was significantly upregulated in tumor tissues, and silencing DEPDC1B could inhibit proliferation, migration and promote apoptosis of GBM cell. In addition, human apoptosis antibody array detection showed that after DEPDC1B knockdown, the expression of apoptosis-related proteins was downregulated, such as IGFBP-2, Survivin, N-cadherin, Vimentin and Snail. Finally, we indicated that knockdown of DEPDC1B significantly inhibited tumor growth in vivo.
    Conclusions: In summary, DEPDC1B was involved in the development and progression of GBM, which may be a potential therapeutic target and bring a breakthrough in the treatment.
    Keywords:  Apoptosis; DEPDC1B; GBM; Migration; Proliferation
    DOI:  https://doi.org/10.1186/s12935-020-01404-7
  7. Glia. 2020 Jul 25.
    Maleszewska M, Steranka A, Smiech M, Kaza B, Pilanc P, Dabrowski M, Kaminska B.
      Microglia, resident myeloid cells of the central nervous system (CNS), act as immune sentinels that contribute to maintenance of physiological homeostasis and respond to any perturbation in CNS. Microglia could be polarized by various stimuli to perform dedicated functions and instigate inflammatory or pro-regenerative responses. Microglia and peripheral macrophages accumulate in glioblastomas (GBMs), malignant brain tumors, but instead of initiating antitumor responses, these cells are polarized to the pro-invasive and immunosuppressive phenotype which persists for a long time and contributes to a "cold" immune microenvironment of GBMs. Molecular mechanisms underlying this long-lasting "microglia memory" are unknown. We hypothesized that this state may rely on epigenetic silencing of inflammation-related genes. In this study, we show that cultured microglia pre-exposed to glioma-conditioned medium (GCM) acquire a "transcriptional memory" and display reduced expression of inflammatory genes after re-stimulation with lipopolysaccharide. Unstimulated microglia have unmethylated DNA and active histone marks at selected gene promoters indicating chromatin accessibility. Adding GCM increases expression and enzymatic activity of histone deacetylases (Hdac), leading to erasure of histone acetylation at tested genes. Later inflammatory genes acquire repressive histone marks (H3K27 trimethylation), which correlates with silencing of their expression. GCM induced genes acquire active histone marks. Hdac inhibitors block GCM-induced changes of histone modifications and restore microglia ability to initiate effective inflammatory responses. Altogether, we show a scenario of distinct histone modifications underlying polarization of microglia by glioma. We demonstrate contribution of epigenetic mechanisms to glioma-induced "transcriptional memory" in microglia resulting in the tumor-supportive phenotype.
    Keywords:  DNA methylation; glioma-associated activation; histone deacetylases; histone modification; inflammation-related genes; microglia
    DOI:  https://doi.org/10.1002/glia.23887
  8. Nat Commun. 2020 Jul 22. 11(1): 3669
    Li Y, Li B, Li W, Wang Y, Akgül S, Treisman DM, Heist KA, Pierce BR, Hoff B, Ho CY, Ferguson DO, Rehemtulla A, Zheng S, Ross BD, Li JZ, Zhu Y.
      Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we show two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grow as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues reveals no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 are observed in the subventricular zone (SVZ), but are distantly segregated from multi focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocks distant dispersal, restricting glioma growth in the SVZ.
    DOI:  https://doi.org/10.1038/s41467-020-17382-3
  9. Biochem Biophys Res Commun. 2020 Aug 20. pii: S0006-291X(20)31192-X. [Epub ahead of print]529(2): 162-168
    Smits IPM, Blaschuk OW, Willerth SM.
      Glioblastoma multiforme (GBM) is a deadly type of brain cancer. There is a need to identify novel therapies for GBM as current treatments only marginally increase survival. Modelling the complexity of cancerous tissues using 3D bioprinted constructs serves as a novel approach for preclinical testing of anticancer drugs. A novel small molecule antagonist of the cell adhesion molecule, N-cadherin (NCAD), (S)-1-(3,4-Dichlorophenoxy)-3-(4-((S)-2-hydroxy-3-(4-methoxyphenoxy)propylamino)piperidin-1-yl)propan-2-ol has shown promise as an anticancer agent. This study investigated the influence of this antagonist on GBM cells bioprinted with astrocytes into 3D constructs. The NCAD antagonist prevented spheroid formation and induced cell death in the 3D model. This is the first demonstration that an NCAD antagonist can cause GBM cell death.
    Keywords:  3D tumor model; Bioprinting; Glioblastoma; N-cadherin
    DOI:  https://doi.org/10.1016/j.bbrc.2020.06.001
  10. Clin Cancer Res. 2020 Jul 21. pii: clincanres.0736.2020. [Epub ahead of print]
    Ye Z, Price RL, Liu X, Lin J, Yang Q, Sun P, Wu AT, Wang L, Han RH, Song C, Yang R, Gary SE, Mao DD, Wallendorf M, Campian JL, Li JS, Dahiya S, Kim AH, Song SV.
      PURPOSE: Glioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted for examining GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of GBMs.EXPERIMENTAL DESIGN: We employ a novel Diffusion Histology Imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM.
    RESULTS: Gd-enhanced T1W or hyper-intense FLAIR failed to reflect the morphological complexity underlying tumor in GBM patients. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in glioblastoma specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0% and 93.4% accuracy, respectively.
    CONCLUSIONS: Our results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques for guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of glioblastoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-0736
  11. Neurol Res. 2020 Jul 24. 1-9
    Tsitlakidis A, Aifantis EC, Kritis A, Tsingotjidou AS, Cheva A, Selviaridis P, Foroglou N.
      Brain gliomas represent some of the most aggressive tumors encountered by modern medicine and, despite major efforts to optimize early diagnosis and treatment, the prognosis remains poor. Due to the complex structure of the brain and the unique mechanical properties of the extracellular matrix, gliomas invade and expand into the brain parenchyma, along white matter tracts and within perivascular spaces, usually sparing normal vessels. Different methods have been developed to study the mechanical properties of gliomas in a wide range of scales, from cells and the microscale to tissues and the macroscale. In this review, the current view on glioma mechanics is presented and the methods used to determine glioma mechanical properties are outlined. Their principles and current state of affairs are discussed.
    Keywords:  Glioma; atomic force microscope; elasticity; magnetic resonance elastography; mechanobiology; ultrasound elastography
    DOI:  https://doi.org/10.1080/01616412.2020.1796381
  12. Sci Rep. 2020 Jul 23. 10(1): 12272
    Lee YJ, Seo HW, Baek JH, Lim SH, Hwang SG, Kim EH.
      Glioblastoma is frequently associated with TP53 mutation, which is linked to a worse prognosis and response to conventional treatments (chemoradiotherapy). Therefore, targeting TP53 is a promising strategy to overcome this poor therapeutic response. Tumor-treating fields (TTFields) are a recently approved treatment for newly diagnosed glioblastoma, which involves direct application of low-intensity, intermediate-frequency alternating electric fields to the tumor, thereby offering a local tumor-killing effect. However, the influence of TP53 mutation status on the effectiveness of TTFields is controversial. Here, we identified the key gene signatures and pathways associated with TTFields in four glioblastoma cell lines varying in TP53 mutation status using gene profiling and functional annotation. Overall, genes associated with the cell cycle, cell death, and immune response were significantly altered by TTFields regardless of TP53 status. TTFields appeared to exert enhanced anti-cancer effects by altering the immune system in the inflammatory environment and regulating cell cycle- and cell death-related genes, but the precise genes influenced vary according to TP53 status. These results should facilitate detailed mechanistic studies on the molecular basis of TTFields to further develop this modality as combination therapy, which can improve the therapeutic effect and minimize side effects of chemoradiotherapy.
    DOI:  https://doi.org/10.1038/s41598-020-68473-6
  13. Int J Mol Sci. 2020 Jul 21. pii: E5167. [Epub ahead of print]21(14):
    Palma A, Grande S, Ricci-Vitiani L, Luciani AM, Buccarelli M, Biffoni M, Dini V, Cirrone GAP, Ciocca M, Guidoni L, Pallini R, Viti V, Rosi A.
      Glioblastoma multiforme (GBM) is a malignant primary brain tumor with very poor prognosis, high recurrence rate, and failure of chemo-radiotherapy, mainly due to a small fraction of cells with stem-like properties (GSCs). To study the mechanisms of GSCs resistance to radiation, two GSC lines, named line #1 and line #83, with different metabolic patterns and clinical outcome, were irradiated with photon beams and carbon ions and assessed by 1H Magnetic Resonance Spectroscopy (MRS). Both irradiation modalities induced early cytotoxic effects in line #1 with small effects on cell cycle, whereas a proliferative G2/M cytostatic block was observed in line #83. MR spectroscopy signals from mobile lipids (ML) increased in spectra of line #1 after photon and C-ion irradiation with effects on lipid unsaturation level, whereas no effects were detected in line #83 spectra. Gamma-Aminobutyric Acid (GABA), glutamic acid (glu) and Phosphocreatine (pCr) signals showed a significant variation only for line #1 after carbon ion irradiation. Glucose (glc) level and lactate (Lac) extrusion behaved differently in the two lines. Our findings suggest that the differences in irradiation response of GSCs #1 and #83 lines are likely attributable to their different metabolic fingerprint rather than to the different radiation types.
    Keywords:  MRS; carbon ions; glioblastoma; metabolism; photon beams; stem cells
    DOI:  https://doi.org/10.3390/ijms21145167
  14. Cancers (Basel). 2020 Jul 17. pii: E1935. [Epub ahead of print]12(7):
    Tabouret E, Wang H, Amin N, Jung J, Appay R, Cui J, Song Q, Cardone A, Park DM, Gilbert MR, Pant H, Zhuang Z.
      We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.
    Keywords:  ATM; CDK5; DNA damage; chemotherapy; glioblastoma; radiotherapy; targeted therapy
    DOI:  https://doi.org/10.3390/cancers12071935