Oncogene cooperation in glioma genesis

癌基因在神经胶质瘤发生中的合作

• 批准号: 7790987
• 负责人: GREGORY Neal FULLER
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790987
• 关键词: Adopted; Allografting; Anaplastic astrocytoma; Animal Model; Apoptosis; Area; Astrocytoma; Atlases; Biological Models; Brain; Candidate Disease Gene; Cell Culture System; Cell Proliferation; Cells; Cellularity; Complex; Development; Diagnosis; Endothelial Cells; Environment; Evaluation; Event; GRB2 gene; Gene Combinations; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genomics; Glioblastoma; Glioma; Gliomagenesis; Growth Factor; Human; IGFBP2 gene; Informatics; Knowledge; Lead; Life; Light; Malignant Neoplasms; Modeling; Molecular; Molecular Genetics; Mus; Mutate; Oncogenes; Oncogenic; PDGFB gene; Pathway Analysis; Pathway interactions; Patients; Phenotype; Process; Refractory; Research; Resources; Small Interfering RNA; Somatic Gene Therapy; Staging; Suppressor Genes; System; Testing; Therapeutic; Therapeutic Uses; Transgenic Mice; Transgenic Organisms; Translating; Translations; Tumor Suppressor Genes; Tumor Tissue; Validation; Vascular Endothelial Growth Factors; Vascular Proliferation; angiogenesis; base; beta Subunit Transducin; c-myc Genes; cancer genome; cancer genomics; cell motility; clinical application; comparative; effective therapy; gene interaction; in vivo Model; mathematical model; mouse model; neoplastic cell; novel; oligodendroglioma; overexpression; pre-clinical; programs; public health relevance; research study; small hairpin RNA; therapeutic target; tool; tumor; tumor progression; tumorigenesis; validation studies

DESCRIPTION (provided by applicant): Cancer development and progression involve activation of multiple oncogenes and inactivation of multiple tumor suppressor genes. Many oncogenes enhance cell proliferation, inhibit apoptosis, and promote angiogenesis and invasion (the hallmarks of cancer). In contrast, tumor suppressor genes inhibit proliferation, enhance apoptosis, and inhibit cell migration and invasion. It is becoming increasingly clear that activated oncogenes do not act singly in isolation to manifest the hallmarks of cancer progression; rather, oncogene and tumor suppressor gene interaction, i.e., oncogene cooperation, comprises a critical oncogenic mechanism. Cancer development and progression also involve close interaction between tumor cells and constituents of their environment, such as the interaction with endothelial cells in the promotion of angiogenesis. These important and complex processes are difficult to elucidate through study of simple cell culture systems alone. Mouse models have thus become an instrumental tool for characterizing oncogenes and tumor suppressor genes, their interactions and cooperation, and the interactions between tumor cells and their environmental milieu. Gliomas represent the single most frequent type of primary brain malignancy. The most advanced form of glioma, and also the most invasive and refractory to therapy, is glioblastoma (GBM), which comprises 50-60% of all gliomas. The median survival for GBM patients is less than a year. Only about 20% of patients respond to therapy and live for more than 1.5 years following initial diagnosis. Primary GBMs are believed to develop de novo. Secondary GBMs are believed to arise through anaplastic progression from lower grade astrocytomas (anaplastic astrocytoma, AA; and low-grade astrocytoma, A). Intensive research over the last three decades, especially recent genomics research (The Cancer Genome Atlas on glioblastoma), has revealed a large number of putative oncogenes that are amplified and overexpressed in glioma, as well as putative glioma tumor suppressor genes that are deleted, diminished, or mutated. However, the very productive high- throughput genomic discovery process has not been matched by corresponding validation studies aimed at the functional characterization of the newly discovered putative cancer genes and their cooperative interactions. We have employed a powerful glial-specific mouse model (the RCAS/tv-a system) to characterize oncogenic events in gliomagenesis. RCAS/tv-a is a somatic gene transfer model that permits transgenic expression of multiple genes in a single experimental setting, thus allowing evaluation of oncogene cooperation. Whereas multiple genetic and molecular events are usually required for oncogenesis in humans, in mice 2 or 3 strong cooperative events are often sufficient to induce tumorigenesis; thus, animal models have been useful for identifying specific cooperative interactions critical for tumor formation and for specific tumor phenotype generation. Using genomics and informatics approaches, we have profiled gene expression in different grades of glioma and identified genes in different cellular pathways that are overexpressed in different glioma grades. We hypothesize that the signature genes in cell proliferation, cell invasion, and angiogenesis are part of key oncogene cooperation systems that are crucial for glioma progression. The novelty of the proposed studies is to test this hypothesis, and to identify key interactive and cooperative gliomagenesis genes using the RCAS/tv-a mouse model. Knowledge gained from this study will impact development of pathway-oriented therapeutics, especially for GBM, in which effective therapy is most needed. PUBLIC HEALTH RELEVANCE: In order to find effective targets for glioma treatment, we have to understand the cooperative oncogenes that are underlying glioma genesis and progression. This is the key mechanism for cancer phenotypes however quite understudied in the field. The major bottleneck is lack of robust in vivo models. Our previous studies have proven that the RCAS-tva model system would allow us to systematically interrogate oncogene cooperation in a relatively low throughput fashion. Thus, this study is novel and will shift paradigm and important therapeutic strategy for glioma, especially GBM. We will characterize the pathways of gliomas generated and begin our effort to target the identified pathway for therapeutics using siRNA/shRNA, pharmacological, and allograft model strategies. Thus, this proposed study will not only study mechanism of glioma genesis and progression but will also translate the pathway understanding to pre-clinical application.

描述（由申请人提供）：癌症的发展和进展涉及多种肿瘤基因的激活以及多种肿瘤抑制基因的失活。许多肿瘤基因增强细胞增殖，抑制凋亡并促进血管生成和侵袭（癌症的标志）。相反，肿瘤抑制基因抑制增殖，增强凋亡并抑制细胞迁移和侵袭。越来越清楚的是，激活的癌基因并不能单独起作用以表现出癌症进展的标志。相反，癌基因和肿瘤抑制基因相互作用，即癌基因合作，包括关键的致癌机制。癌症的发展和进展还涉及肿瘤细胞与其环境成分之间的密切相互作用，例如在促进血管生成中与内皮细胞的相互作用。仅通过研究简单的细胞培养系统，这些重要而复杂的过程很难阐明。因此，小鼠模型已成为表征癌基因和肿瘤抑制基因的工具工具，它们的相互作用和合作以及肿瘤细胞与其环境环境之间的相互作用。神经胶质瘤代表最常见的原发性脑恶性肿瘤类型。胶质母细胞瘤（GBM）最先进的神经胶质瘤形式，也是最具侵入性和难治性的治疗，其中占所有神经胶质瘤的50-60％。 GBM患者的中位生存期不到一年。初始诊断后，只有约20％的患者对治疗做出反应，并在1。5年以上生活。据信初级GBM会发展起来。据信，次级GBM是通过低级星形胶质细胞瘤（播种星形胶质细胞瘤，AA；和低级星形胶质细胞瘤，a）的偏移进展而产生的。在过去的三十年中，尤其是最近的基因组学研究（胶质母细胞瘤上的癌症基因组图集）的深入研究表明，大量推定的癌基因基因在神经胶质瘤中被放大和过表达，以及被删除，降低，降低，或突变的假定神经胶质瘤抑制基因。但是，旨在旨在新发现的假定癌症基因及其合作相互作用的相应验证研究尚未匹配非常有生产力的高吞吐基因组发现过程。我们采用了强大的神经胶质特异性小鼠模型（RCAS/TV-A系统）来表征神经胶质作用中的致癌事件。 RCAS/TV-A是一种体细胞基因转移模型，允许在单个实验环境中多个基因的转基因表达，从而可以评估癌基因合作。尽管人类肿瘤发生通常需要多个遗传事件和分子事件，但在2或3只强大的合作事件中，通常足以诱导肿瘤发生。因此，动物模型对于确定对肿瘤形成和特定肿瘤表型产生至关重要的特定合作相互作用很有用。使用基因组学和信息学方法，我们在不同级别的神经胶质瘤中介绍了基因表达，并在不同的细胞途径中鉴定出基因在不同的胶质瘤等级中过表达的基因。我们假设细胞增殖，细胞侵袭和血管生成中的特征基因是对神经胶质瘤进展至关重要的关键致癌基因合作系统的一部分。拟议的研究的新颖性是检验该假设，并使用RCAS/TV-A小鼠模型鉴定关键的互动和合作神经胶质作用基因。从这项研究中获得的知识将影响面向途径的治疗剂的发展，尤其是对于最需要有效治疗的GBM。 公共卫生相关性：为了找到有效的神经胶质瘤治疗靶标，我们必须了解基础神经胶质瘤起源和进展的合作致癌基因。这是癌症表型的关键机制，但是在该领域已经详细研究了。主要的瓶颈是体内模型缺乏强大的瓶颈。我们以前的研究已经证明，RCAS-TVA模型系统将使我们以相对较低的吞吐量方式系统地询问癌基因合作。因此，这项研究是新颖的，将改变胶质瘤，尤其是GBM的重要治疗策略。我们将表征生成的神经胶质瘤的途径，并开始使用siRNA/SHRNA，药理学和同种异体移植模型策略来瞄准已识别的治疗途径。因此，这项提出的研究不仅将研究神经胶质瘤起源和进展的机制，而且还将将途径理解转化为临床前应用。