Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II–IV. ...Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, which included the transcription factor SIX1 and its principal cofactors, EYA1 and DACH2. Small hairpin RNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs with those of normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood and more specifically targeted.
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•Gene expression in normal versus neoplastic A2B5+ glioma tumor progenitor cells (TPCs) was profiled•A2B5+ TPCs transit from proneural to mesenchymal phenotype with glioma progression•SIX1 and EYA1 are overexpressed in A2B5+ TPCs at all stages of glioma progression•Inhibition of SIX1 suppresses glioma TPC expansion in vitro and in vivo
A discrete fraction of tumor progenitor cells (TPCs) may be responsible for the initiation, recurrence, and treatment resistance of glioma. To identify pathways to treat these tumors, Auvergne, Goldman, and colleagues compared the expression profiles of A2B5-defined glioma TPCs at varying stages of progression with those of normal adult human glial progenitor cells. They identify a discrete cohort of genes and pathways that are associated with the earliest stages of glioma formation and are maintained throughout progression. Targeting these pathways may permit more effective glioma treatment.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are ...no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.
Glioblastoma multiform (GBM) remains clinical indication with significant "unmet medical need". Innovative new therapy to eliminate residual tumor cells and prevent tumor recurrences is critically ...needed for this deadly disease. A major challenge of GBM research has been the identification of novel molecular therapeutic targets and accurate diagnostic/prognostic biomarkers. Many of the current clinical therapeutic targets of immunotoxins and ligand-directed toxins for high-grade glioma (HGG) cells are surface sialylated glycoproteins. Therefore, methods that systematically and quantitatively analyze cell surface sialoglycoproteins in human clinical tumor samples would be useful for the identification of potential diagnostic markers and therapeutic targets for malignant gliomas. In this study, we used the bioorthogonal chemical reporter strategy (BOCR) in combination with label-free quantitative mass spectrometry (LFQ-MS) to characterize and accurately quantify the individual cell surface sialoproteome in human GBM tissues, in fetal, adult human astrocytes, and in human neural progenitor cells (NPCs). We identified and quantified a total of 843 proteins, including 801 glycoproteins. Among the 843 proteins, 606 (72%) are known cell surface or secreted glycoproteins, including 156 CD-antigens, all major classes of cell surface receptor proteins, transporters, and adhesion proteins. Our findings identified several known as well as new cell surface antigens whose expression is predominantly restricted to human GBM tumors as confirmed by microarray transcription profiling, quantitative RT-PCR and immunohistochemical staining. This report presents the comprehensive identification of new biomarkers and therapeutic targets for the treatment of malignant gliomas using quantitative sialoglycoproteomics with clinically relevant, patient derived primary glioma cells.
Non-Stem Cell Origin for Oligodendroglioma Persson, Anders I.; Petritsch, Claudia; Swartling, Fredrik J. ...
Cancer cell,
12/2010, Letnik:
18, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. ...Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.
► Progenitor rather than stem cell origin for oligodendroglioma ► Oligodendroglioma display properties of oligodendrocyte progenitor cells ► Distinguishing characteristics between oligodendroglioma and astrocytoma cells
Sox2 is expressed by neural stem and progenitor cells, and a sox2 enhancer identifies these cells in the forebrains of both fetal and adult transgenic mouse reporters. We found that an adenovirus ...encoding EGFP placed under the regulatory control of a 0.4 kb sox2 core enhancer selectively identified multipotential and self-renewing neural progenitor cells in dissociates of human fetal forebrain. Upon EGFP-based fluorescence-activated cell sorting (FACS), the E/sox2:EGFP(+) isolates were propagable for up to 1 year in vitro, and remained multilineage competent throughout. E/sox2:EGFP(+) cells expressed more telomerase enzymatic activity than matched E/sox2:EGFP-depleted populations, and maintained their telomeric lengths with successive passage. Gene expression analysis of E/sox2:EGFP-sorted neural progenitor cells, normalized to the unsorted forebrain dissociates from which they derived, revealed marked overexpression of genes within the notch and wnt pathways, and identified multiple elements of each pathway that appear selective to human neural progenitors. Sox2 enhancer-based FACS thus permits the prospective identification and direct isolation of a telomerase-active population of neural stem cells from the human fetal forebrain, and the elucidation of both the transcriptome and dominant signaling pathways of these critically important cells.
In a comparison of gene expression by A2B5-defined glial tumor progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain (Cell Reports 3:2127-41, 2013), we found that ...the F2R gene encoding PAR1 was differentially over-expressed by TPCs isolated from primary gliomas at every stage of glioma progression. In this study, we therefore asked if PAR1 activation was causally associated with glioma progression. Lentiviral shRNAi knock-down of PAR1 inhibited the expansion and proliferation of glioma TPCs in vitro. We further found that the PAR-1 receptor antagonists SCH79797 and SCH530348 (vorapaxar) inhibited A2B5
+
TPC expansion and migration in vitro. PAR1 knockdown also suppressed the tumorigenic potential of A2B5
+
TPCs after transplantation into the brains of immunodeficient mice. In addition, mice given subcutaneous grafts of A2B5
+
human glioma TPCs exhibited delayed tumor growth if treated with Vorapaxar, relative to xenografted control mice treated with only vehicle. Together, these data suggest that PAR1 may contribute to glioma progenitor expansion and tumor growth; as such, the abrogation of PAR1 signaling may contribute to the treatment of malignant glioma.
In a comparison of gene expression by A2B5-defined glial tumor progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain (Cell Reports 3:2127-41, 2013), we found that ...the F2R gene encoding PAR1 was differentially over-expressed by TPCs isolated from primary gliomas at every stage of glioma progression. In this study, we therefore asked if PAR1 activation was causally associated with glioma progression. Lentiviral shRNAi knock-down of PAR1 inhibited the expansion and proliferation of glioma TPCs in vitro. We further found that the PAR-1 receptor antagonists SCH79797 and SCH530348 (vorapaxar) inhibited A2B5+ TPC expansion and migration in vitro. PAR1 knockdown also suppressed the tumorigenic potential of A2B5+ TPCs after transplantation into the brains of immunodeficient mice. In addition, mice given subcutaneous grafts of A2B5+ human glioma TPCs exhibited delayed tumor growth if treated with Vorapaxar, relative to xenografted control mice treated with only vehicle. Together, these data suggest that PAR1 may contribute to glioma progenitor expansion and tumor growth; as such, the abrogation of PAR1 signaling may contribute to the treatment of malignant glioma.
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