RESUMO
Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPCs have the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Neurais/patologia , Oligodendroglia/patologia , Oligodendroglioma/patologia , Animais , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem da Célula , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Oligodendroglia/metabolismo , Oligodendroglioma/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Vimentina/metabolismoRESUMO
The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/genética , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Adulto , Idoso , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p19/deficiência , Inibidor de Quinase Dependente de Ciclina p19/genética , Intervalo Livre de Doença , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Nestina/genética , Nestina/metabolismo , Células Tumorais CultivadasRESUMO
Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.
Assuntos
Bancos de Espécimes Biológicos , Glioblastoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Análise por Conglomerados , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Instabilidade Genômica , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/cirurgia , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Células Tumorais Cultivadas , Adulto JovemRESUMO
Platelet-derived growth factor B (PDGF-B) is a growth factor promoting and regulating cell migration, proliferation, and differentiation, involved in both developmental processes and in maintaining tissue homeostasis under strict regulation. What are the implications of prolonged or uncontrolled growth factor signaling in vivo, and when does a growth factor such as PDGF-B become an oncogene? Under experimental conditions, PDGF-B induces proliferation and causes tumor induction. It is not known whether these tumors are strictly a PDGF-B-driven proliferation of cells or associated with secondary genetic events such as acquired mutations or methylation-mediated gene silencing promoting neoplasia. If PDGF-B-driven tumorigenesis was only cellular proliferation, associated changes in gene expression would thus be correlated with proliferation and not associated with secondary events involved in tumorigenesis and neoplastic transformation such as cycle delay, DNA damage response, and cell death. Changes in gene expression might be expected to be reversible, as is PDGF-B-driven proliferation under normal circumstances. Since PDGF signaling is involved in oligodendrocyte progenitor cell differentiation and maintenance, it is likely that PDGF-B stimulates proliferation of a pool of cells with that phenotype, and inhibition of PDGF-B signaling would result in reduced expression of oligodendrocyte-associated genes. More importantly, inhibition of PDGF signaling would be expected to result in reversion of genes induced by PDGF-B accompanied by a decrease in proliferation. However, if PDGF-B-driven tumorigenesis is more than simply a proliferation of cells, inhibition of PDGF signaling may not reverse gene expression or halt proliferation. These fundamental questions concerning PDGF-B as a potential oncogene have not been resolved.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioma/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Neoplasias Encefálicas/patologia , Diferenciação Celular , Divisão Celular , Glioma/patologia , Humanos , Oncogenes , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de SinaisRESUMO
Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.
Assuntos
Neoplasias Encefálicas/prevenção & controle , Instabilidade Genômica , Glioma/prevenção & controle , Hiperplasia/prevenção & controle , Proteínas Proto-Oncogênicas c-sis/metabolismo , Rad51 Recombinase/metabolismo , Fator 1 de Ribosilação do ADP/fisiologia , Animais , Western Blotting , Encéfalo/citologia , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Galinhas , Dano ao DNA , Reparo do DNA , Replicação do DNA , Fibroblastos/citologia , Fibroblastos/metabolismo , Citometria de Fluxo , Glioma/genética , Glioma/patologia , Proteínas de Fluorescência Verde/genética , Recombinação Homóloga , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Técnicas Imunoenzimáticas , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-sis/genética , Rad51 Recombinase/genética , Células-Tronco/metabolismoRESUMO
Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).