Oncogene cooperation in glioma genesis

癌基因在神经胶质瘤发生中的合作

基本信息

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
项目类别：
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

项目摘要

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）：癌症的发生和进展涉及多种癌基因的激活和多种抑癌基因的失活。许多癌基因增强细胞增殖、抑制细胞凋亡、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，增强细胞凋亡，并抑制细胞迁移和侵袭。越来越清楚的是，激活的癌基因不会单独单独发挥作用来表现出癌症进展的特征；相反，癌基因和抑癌基因的相互作用，即癌基因的合作，构成了关键的致癌机制。癌症的发生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，例如与内皮细胞的相互作用促进血管生成。这些重要而复杂的过程很难仅通过研究简单的细胞培养系统来阐明。因此，小鼠模型已成为表征癌基因和抑癌基因、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的工具。神经胶质瘤是最常见的原发性脑恶性肿瘤类型。最晚期的神经胶质瘤形式，也是最具侵袭性和难治性的，是胶质母细胞瘤 (GBM)，占所有神经胶质瘤的 50-60%。 GBM 患者的中位生存期不到一年。只有约 20% 的患者对治疗有反应，并在初次诊断后存活超过 1.5 年。原发性 GBM 被认为是从头形成的。继发性 GBM 被认为是由低级别星形细胞瘤（间变性星形细胞瘤，AA；和低级别星形细胞瘤，A）的间变性进展引起的。过去三十年的深入研究，特别是最近的基因组学研究（胶质母细胞瘤癌症基因组图谱），揭示了大量在胶质瘤中扩增和过度表达的假定癌基因，以及被删除、减少的假定胶质瘤抑癌基因，或突变。然而，非常富有成效的高通量基因组发现过程尚未与旨在新发现的假定癌症基因的功能表征及其协同相互作用的相应验证研究相匹配。我们采用了强大的神经胶质特异性小鼠模型（RCAS/tv-a 系统）来表征神经胶质瘤发生中的致癌事件。 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转基因表达多个基因，从而可以评估癌基因的合作。人类的肿瘤发生通常需要多种遗传和分子事件，而在小鼠中，2或3个强协同事件通常足以诱导肿瘤发生；因此，动物模型可用于识别对肿瘤形成和特定肿瘤表型生成至关重要的特定合作相互作用。使用基因组学和信息学方法，我们分析了不同级别的神经胶质瘤中的基因表达，并鉴定了不同细胞通路中在不同级别的神经胶质瘤中过度表达的基因。我们假设细胞增殖、细胞侵袭和血管生成的特征基因是对神经胶质瘤进展至关重要的关键癌基因合作系统的一部分。本研究的新颖之处在于检验这一假设，并使用 RCAS/tv-a 小鼠模型来识别关键的相互作用和协作的神经胶质瘤发生基因。从这项研究中获得的知识将影响路径导向疗法的发展，特别是对于 GBM，其中最需要有效的治疗。公共卫生相关性：为了找到神经胶质瘤治疗的有效靶点，我们必须了解神经胶质瘤发生和进展的协同癌基因。这是癌症表型的关键机制，但该领域尚未得到充分研究。主要瓶颈是缺乏稳健的体内模型。我们之前的研究已经证明，RCAS-tva 模型系统将使我们能够以相对低通量的方式系统地询问癌基因的合作。因此，这项研究是新颖的，将改变神经胶质瘤，特别是 GBM 的范式和重要的治疗策略。我们将描述神经胶质瘤产生的途径，并开始努力使用 siRNA/shRNA、药理学和同种异体移植模型策略来针对已确定的治疗途径。因此，这项研究不仅将研究神经胶质瘤发生和进展的机制，还将对通路的理解转化为临床前应用。