RESUMO
Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin ß1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients.
Assuntos
Neoplasias Encefálicas/patologia , Terapia Genética , Vetores Genéticos/uso terapêutico , Glioblastoma/patologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Integrina beta1/fisiologia , NF-kappa B/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Proteínas Aviárias/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Genes Sintéticos , Genes sis , Vetores Genéticos/administração & dosagem , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/toxicidade , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/toxicidade , Proteínas de Filamentos Intermediários/genética , Estimativa de Kaplan-Meier , Camundongos , Camundongos Transgênicos , Inibidor de NF-kappaB alfa , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Nestina , Oligodendroglioma/genética , Oligodendroglioma/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/toxicidade , Receptores Virais/genética , Retroviridae , Transdução de Sinais/fisiologiaRESUMO
The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development and progression.
Assuntos
Neoplasias Encefálicas/genética , Modelos Animais de Doenças , Glioma/genética , Oncogenes/genética , Animais , Vírus da Leucose Aviária/genética , Proteínas Aviárias/genética , Neoplasias Encefálicas/patologia , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos/métodos , Vetores Genéticos , Glioma/patologia , Humanos , Camundongos , Camundongos Transgênicos , Receptores Virais/genéticaRESUMO
The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-beta (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16(INK4a) and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16(INK4a) is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-sis/metabolismoRESUMO
The genetic consequences resulting from environmental exposure to ionizing radiation have a significant impact on both radiation regulatory policies and the comprehension of the human health risks associated with radiation exposure. The primary objectives of the study were to assess 1) genotoxicity of exposure to radiation as a function of absorbed dose and dose rate, and 2) induction of a radio-adaptive response following a priming dose at varying dose rates. Results demonstrated that sub-acute environmental exposures of 10cGy gamma radiation resulted in indistinguishable levels of chromosomal damage as compared to controls. A radio-adaptive response was observed in all experimental groups, exposed to a subsequent acute challenge dose of 1.5 Gy, demonstrating that low dose rates of low energy transfer (LET) radiation are effective in reducing genetic damage from a subsequent acute low-LET radiation exposure. Furthermore, the data presented herein demonstrate a potential beneficial effect of sub-chronic exposure to low levels of low-LET radiation in an environmental setting and do not support the Linear No Threshold (LNT) hypothesis.
