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In recent years, liquid biopsy has emerged as an alternative method to diagnose and monitor tumors. Compared to classical tissue biopsy procedures, liquid biopsy facilitates the repetitive collection of diverse cellular and acellular analytes from various biofluids in a non/minimally invasive manner. This strategy is of greater significance for high-grade brain malignancies such as glioblastoma as the quantity and accessibility of tumors are limited, and there are collateral risks of compromised life quality coupled with surgical interventions. Currently, blood and cerebrospinal fluid (CSF) are the most common biofluids used to collect circulating cells and biomolecules of tumor origin. These liquid biopsy analytes have created opportunities for real-time investigations of distinct genetic, epigenetic, transcriptomics, proteomics, and metabolomics alterations associated with brain tumors. This review describes different classes of liquid biopsy biomarkers present in the biofluids of brain tumor patients. Moreover, an overview of the liquid biopsy applications, challenges, recent technological advances, and clinical trials in the brain have also been provided.
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Neoplasias Encefálicas , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patologia , Biópsia Líquida/métodos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Encéfalo/patologia , Biomarcadores Tumorais/genéticaRESUMO
Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.
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Neoplasias Encefálicas/metabolismo , Distroglicanas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Microambiente Tumoral/fisiologia , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/cirurgia , Transformação Celular Neoplásica , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Glioma/irrigação sanguínea , Glioma/cirurgia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de NeoplasiasRESUMO
Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.
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Neoplasias Encefálicas/fisiopatologia , Glioma/fisiopatologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Neoplásicas/citologia , Fatores de Transcrição/metabolismo , Aciltransferases , Animais , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Epigenômica , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes. SIGNIFICANCE STATEMENT: Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify â¼50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development.
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Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Glioblastoma/classificação , Glioblastoma/metabolismo , MicroRNAs/biossíntese , Fatores de Transcrição SOXB1/biossíntese , Animais , Biomarcadores Tumorais/biossíntese , Neoplasias Encefálicas/diagnóstico , Células Cultivadas , Glioblastoma/diagnóstico , Humanos , Masculino , Camundongos , Camundongos Nus , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. Unexpectedly, homozygous mutant mice died before E7.5, and deletion of p53 rescued the lethality. Furthermore, reintroducing a switchable p53 by crossing with p53ER(TAM) mice surprisingly demonstrated that the mutant Mdm2(C462A) was rapidly degraded in a manner indistinguishable from that of the wild-type Mdm2. Hence, our data indicate that (1) the Mdm2-p53 physical interaction, without Mdm2-mediated p53 ubiquitination, cannot control p53 activity sufficiently to allow early mouse embryonic development, and (2) Mdm2's E3 function is not required for Mdm2 degradation.
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Regulação da Expressão Gênica no Desenvolvimento , Mutagênese Sítio-Dirigida , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo , Substituição de Aminoácidos , Animais , Células Cultivadas , Dano ao DNA , Regulação para Baixo , Embrião de Mamíferos , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Raios gama , Regulação da Expressão Gênica no Desenvolvimento/efeitos da radiação , Genótipo , Idade Gestacional , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/genética , Transcrição Gênica/efeitos da radiação , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genéticaRESUMO
The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.
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Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.
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Interleucina-17 , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Receptores de Interleucina-17/genética , Camundongos Knockout , Transdução de Sinais , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation. METHODS: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across myeloid subpopulations. Using 2 distinct murine glioma models, we examined the role of Trem2 on tumor progression and immune modulation of myeloid cells. Furthermore, we designed a method of tracking phagocytosis of glioma cells in vivo and employed in vitro assays to mechanistically understand the influence of TREM2 signaling on tumor uptake. RESULTS: We discovered that TREM2 expression does not correlate with immunosuppressive pathways, but rather showed strong a positive association with the canonical phagocytosis markers lysozyme (LYZ) and macrophage scavenger receptor (CD163) in gliomas. While Trem2 deficiency was found to be dispensable for gliomagenesis, Trem2+ myeloid cells display enhanced tumor uptake compared to Trem2- cells. Mechanistically, we demonstrate that TREM2 mediates phagocytosis via Syk signaling. CONCLUSIONS: These results indicate that TREM2 is not associated with immunosuppression in gliomas. Instead, TREM2 is an important regulator of phagocytosis that may be exploited as a potential therapeutic strategy for brain tumors.
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Neoplasias Encefálicas , Glioblastoma , Glicoproteínas de Membrana , Fagocitose , Receptores Imunológicos , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Humanos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Microambiente Tumoral , Células Mieloides/metabolismo , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas , Transdução de SinaisRESUMO
BACKGROUND: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. METHODS: In this study, we used sequential single-cell transcriptomics on 144,678 and spectral cytometry on over two million immune cells encompassing 48 human gliomas to decipher their immune landscape. RESULTS: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild-type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide, which is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed Glio-TIME-36) for deconvoluting transcriptomic datasets. CONCLUSIONS: This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications.
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Glioblastomas (GBMs) are tumors of the central nervous system that remain recalcitrant to both standard of care chemo-radiation and immunotherapies. Emerging approaches to treat GBMs include depletion or re-education of innate immune cells including microglia (MG) and macrophages (MACs). Here we show myeloid cell restricted expression of triggering receptor expressed on myeloid cells 2 (TREM2) across low- and high-grade human gliomas. TREM2 expression did not correlate with immunosuppressive pathways, but rather showed strong positive association with phagocytosis markers such as lysozyme (LYZ) and CD163 in gliomas. In line with these observations in patient tumors, Trem2-/- mice did not exhibit improved survival compared to wildtype (WT) mice when implanted with mouse glioma cell lines, unlike observations previously seen in peripheral tumor models. Gene expression profiling revealed pathways related to inflammation, adaptive immunity, and autophagy that were significantly downregulated in tumors from Trem2-/- mice compared to WT tumors. Using ZsGreen-expressing CT-2A orthotopic implants, we found higher tumor antigen engulfment in Trem2+ MACs, MG, and dendritic cells. Our data uncover TREM2 as an important immunomodulator in gliomas and inducing TREM2 mediated phagocytosis can be a potential immunotherapeutic strategy for brain tumors.
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δ-Catenin is an Armadillo protein of the p120-catenin subfamily capable of modulating cadherin stability, small GTPase activity, and nuclear transcription. From yeast two-hybrid screening of a human embryonic stem cell cDNA library, we identified δ-catenin as a potential interacting partner of the caspase-3 protease, which plays essential roles in apoptotic as well as non-apoptotic processes. Interaction of δ-catenin with caspase-3 was confirmed using cleavage assays conducted in vitro, in Xenopus apoptotic extracts, and in cell line chemically induced contexts. The cleavage site, a highly conserved caspase consensus motif (DELD) within Armadillo repeat 6 of δ-catenin, was identified through peptide sequencing. Cleavage thus generates an amino-terminal (residues 1-816) and carboxyl-terminal (residues 817-1314) fragment, each containing about half of the central Armadillo domain. We found that cleavage of δ-catenin both abolishes its association with cadherins and impairs its ability to modulate small GTPases. Interestingly, 817-1314 possesses a conserved putative nuclear localization signal that may facilitate the nuclear targeting of δ-catenin in defined contexts. To probe for novel nuclear roles of δ-catenin, we performed yeast two-hybrid screening of a mouse brain cDNA library, resolving and then validating interaction with an uncharacterized KRAB family zinc finger protein, ZIFCAT. Our results indicate that ZIFCAT is nuclear and suggest that it may associate with DNA as a transcriptional repressor. We further determined that other p120 subfamily catenins are similarly cleaved by caspase-3 and likewise bind ZIFCAT. Our findings potentially reveal a simple yet novel signaling pathway based upon caspase-3 cleavage of p120-catenin subfamily members, facilitating the coordinate modulation of cadherins, small GTPases, and nuclear functions.
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Apoptose/fisiologia , Caspase 3/metabolismo , Cateninas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/fisiologia , Motivos de Aminoácidos , Animais , Caderinas/genética , Caderinas/metabolismo , Caspase 3/genética , Cateninas/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , Camundongos , Proteínas Nucleares/genética , Estrutura Terciária de Proteína , Proteínas Repressoras/genética , Saccharomyces cerevisiae , Técnicas do Sistema de Duplo-Híbrido , Xenopus laevis , delta CateninaRESUMO
Cell death, be it of neurons or glial cells, marks the development of the nervous system. Albeit relatively less so than in tissues such as the gut, cell death is also a feature of nervous system homeostasis-especially in context of adult neurogenesis. Finally, cell death is commonplace in acute brain injuries, chronic neurodegenerative diseases, and in some central nervous system tumors such as glioblastoma. Recent studies are enumerating the various molecular modalities involved in the execution of cells. Intimately linked with cell death are mechanisms of disposal that remove the dead cell and bring about a tissue-level response. Heretofore, the association between these methods of dying and physiological or pathological responses has remained nebulous. It is envisioned that careful cartography of death and disposal may reveal novel understandings of disease states and chart new therapeutic strategies in the near future.
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Sistema Nervoso , Neurogênese , Adulto , Morte Celular , Homeostase , Humanos , Neurogênese/fisiologia , NeurôniosRESUMO
Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.
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Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.
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Transtorno Autístico/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Instabilidade Genômica/fisiologia , Proteína BRCA1 , Reparo do DNA/fisiologia , Replicação do DNA/genética , Instabilidade Genômica/genética , Humanos , Proto-Oncogene Mas , Proteínas de Ligação a RNA/metabolismo , Rad51 Recombinase/genéticaRESUMO
"Tumor-educated platelets" have recently generated substantial interest for the diagnosis of cancer. We hypothesized that tumor educated platelets from patients with brain tumors will reflect altered metabolism compared to platelets from healthy volunteers. Here, in a pilot study, we have employed nuclear magnetic resonance (NMR) spectroscopy in platelets from brain tumor patients to demonstrate altered metabolism compared to the platelets obtained from healthy volunteers.
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Glioblastoma (GBM) is the most prevalent and aggressive tumor in the central nervous system. Surgical resection followed by concurrent radiotherapy (ionizing radiation [IR]) and temozolomide (TMZ) is the standard of care for GBM. However, a large subset of patients offer resistance or become adapted to TMZ due mainly to the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Thus, alternative mechanisms of MGMT deregulation have been proposed but are heretofore unproven. We show that heterogeneous GBM cells express tunneling nanotubes (TNTs) upon oxidative stress and TMZ/IR treatment. We identified that MGMT protein diffused from resistant to sensitive cells upon exposure to TMZ/IR, resulting in protection against cytotoxic therapy in a TNT-dependent manner. In vivo analysis of resected GBM tumors support our hypothesis that the MGMT protein, but not its mRNA, was associated with TNT biomarkers. We propose that targeting TNT formation could be an innovative strategy to overcome treatment resistance in GBM.
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CNS immune defenses are marshaled and dominated by brain resident macrophages and microglia, which are the innate immune sentinels and frontline host immune barriers against various pathogenic insults. These myeloid lineage cells are the predominant immune population in gliomas and can constitute up to 30-50% of the total cellular composition. Parenchymal microglial cells and recruited monocyte-derived macrophages from the periphery exhibit disease-specific phenotypic characteristics with spatial and temporal distinctions and are heterogeneous subpopulations based on their molecular signatures. A preponderance of myeloid over lymphoid lineage cells during CNS inflammation, including gliomas, is a contrasting feature of brain immunity relative to peripheral immunity. Herein we discuss glioma-associated macrophage and microglia immune biology in the context of their identity, molecular drivers of recruitment, nomenclature and functional paradoxes, therapeutic reprogramming and polarization strategies, relevant challenges, and our perspectives on therapeutic modulation.
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Neoplasias Encefálicas/imunologia , Glioma/imunologia , Macrófagos/imunologia , Microglia/imunologia , Animais , HumanosRESUMO
OBJECTIVE: Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS: Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS: Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS: Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.
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Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Tirosina/metabolismo , Sequência de Bases , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Células Cultivadas , Quimioterapia Adjuvante , Sistemas de Liberação de Medicamentos , Glioma/patologia , Humanos , Imuno-Histoquímica , Metabolômica , Nitrogênio/metabolismo , Tirosina Transaminase/metabolismoRESUMO
BACKGROUND: Glioblastoma (GB) is the most aggressive primary brain tumor, historically resistant to treatment, and with overall fatal outcome. RECENT FINDINGS: Recently, several molecular subgroups and rare genetic alterations have been described in GB. In this review article, we will describe the current clinical management of patients with GB in the United States, discuss selected next-generation molecular-targeted therapies in GB, and present ongoing clinical trials for patients with GB. This review is intended for clinical and preclinical researchers who conduct work on GB and would like to understand more about the current standard of treatment of GB patients, historical perspectives, current challenges, and ongoing and upcoming clinical trials. CONCLUSIONS: GB is an extremely complex disease, and despite recent progress and advanced therapeutic strategies, the overall patient's prognosis remains dismal. Innovative strategies and integrative ways of approach to disease are urgently needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/tendências , Glioblastoma/terapia , Procedimentos Neurocirúrgicos/tendências , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Ensaios Clínicos como Assunto , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Prognóstico , Intervalo Livre de Progressão , Hipofracionamento da Dose de Radiação , Estados Unidos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-ß-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133-/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.