Cytomegalovirus Gene Expression and Strain Variability in Glioma Pathogenesis

胶质瘤发病机制中的巨细胞病毒基因表达和株变异

• 批准号: 8136812
• 负责人: CHARLES S COBBS
• 金额: $ 8.72万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136812
• 关键词: Address; Adult; American; Antiviral Agents; Apoptosis; Biological Assay; Biology; Biopsy; Brain; Brain Neoplasms; Cell Cycle; Cells; Central Nervous System Diseases; Central Nervous System Neoplasms; Characteristics; Cytomegalovirus; Cytomegalovirus Infections; Data; Diagnosis; Disease; Etiology; Exhibits; Fibroblasts; Gene Expression; Genes; Glioblastoma; Glioma; Gliomagenesis; Growth Factor Receptors; Helicobacter pylori; Herpesviridae; Human; Human Herpesvirus 8; Human Papillomavirus; Human Virus; Immune response; Immunocompromised Host; In Vitro; Infection; Infectious Agent; Laboratories; Lead; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Nature; Neuroglia; Nucleic Acids; Oncogenic; PDGFRB gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Prevention strategy; Preventive; Primary Brain Neoplasms; Property; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; Stem cells; TP53 gene; Testing; Tissue Banking; Tissue Banks; Trans-Activators; Tumor Cell Invasion; Tumor Suppressor Proteins; Tumor Tissue; Viral; Viral Genes; Virus; angiogenesis; base; cancer stem cell; cytomegalovirus IE1 protein; design; improved; in utero; in vivo; killings; neoplastic; nerve stem cell; neural precursor cell; neurotropic; novel therapeutics; public health relevance; research study; self-renewal; stem; therapy resistant; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and aggressive form of adult malignant brain cancer, kills 97% of patients within five years. No major advance in determining the etiology or improving therapy has occurred in 50 years. In 2002, we showed that human cytomegalovirus (HCMV) infection occurs in over 90% of GBMs. HCMV is the most common cause of congenital brain infection and encodes for gene products that dysregulate cell cycle, apoptosis, proliferation, immune response, angiogenesis, and cellular invasion. We demonstrated that expression of the essential HCMV IE1 gene can promote proliferation of primary GBM cells (Cobbs et. al. Can Res, 2008) and that activation of PDGFR1, a growth factor receptor implicated in gliomagenesis, is required for infection (Soroceanu et al., Nature, 2008). Our recent preliminary data indicate HCMV infection preferentially occurs in the CD133+ stem-like pool of GBM cells in vivo, and induces genes that sustain the cancer stem cell phenotype. Based on this evidence, we hypothesize HCMV plays a role in initiation and promotion of GBM pathogenesis. We will focus on three essential questions to test our hypothesis: 1) Which HCMV genes are expressed in vivo in GBM and do they promote glioma pathogenesis?, 2) Does HCMV infection induce tumor formation or promote the glioma phenotype in uninfected cells of glial lineage?, and 3) Do "oncogenic" HCMV strains occur in vivo in GBM cells? We will utilize our tumor tissue bank, our extensive in vitro and in vivo brain tumor expertise, and the expertise of collaborators at OHSU and UAB for viral gene array and viral characterization experiments to answer these questions. If we demonstrate that HCMV infection plays a role in the etiology and/or progression of malignant glioma, this paradigm shift in our understanding of this disease will lead to novel therapeutic or even preventive agents for GBM. PUBLIC HEALTH RELEVANCE: Malignant gliomas, which have no known cause, are the most common primary brain tumors, are diagnosed in about 20,000 Americans per year, and are almost 100% fatal within five years. We have discovered that a common human virus, cytomegalovirus (CMV), is found specifically in almost 100% of these tumors and we hypothesize that CMV may cause and / or promote growth of these tumors by expressing genes that drive malignancy. We have planned several experiments that will allow us to determine whether CMV plays a role of CMV in malignant glioma biology - a finding that would have a major impact on our understanding of this cancer and lead to radically new therapies and prevention strategies based on antiviral approaches.

描述（由申请人提供）：多形性胶质母细胞瘤 (GBM) 是成人恶性脑癌最常见和最具侵袭性的形式，五年内导致 97% 的患者死亡。 50 年来，在确定病因或改进治疗方面没有取得重大进展。 2002年，我们发现人类巨细胞病毒（HCMV）感染发生在超过90%的GBM中。 HCMV 是先天性脑部感染的最常见原因，其编码的基因产物可调节细胞周期、细胞凋亡、增殖、免疫反应、血管生成和细胞侵袭。我们证明，必需的 HCMV IE1 基因的表达可以促进原代 GBM 细胞的增殖（Cobbs 等人 Can Res，2008），并且感染需要激活 PDGFR1（一种与神经胶质瘤发生有关的生长因子受体）（Soroceanu 等人，Nature，2008）。我们最近的初步数据表明，HCMV 感染优先发生在体内 GBM 细胞的 CD133+ 干细胞库中，并诱导维持癌症干细胞表型的基因。基于这一证据，我们假设 HCMV 在 GBM 发病机制的启动和促进中发挥作用。我们将重点关注三个基本问题来检验我们的假设：1）哪些 HCMV 基因在 GBM 体内表达，它们是否促进神经胶质瘤发病机制？2）HCMV 感染是否会诱导肿瘤形成或促进神经胶质细胞系未感染细胞的神经胶质瘤表型？3）“致癌”HCMV 株是否在体内 GBM 细胞中出现？我们将利用我们的肿瘤组织库、广泛的体外和体内脑肿瘤专业知识以及 OHSU 和 UAB 合作者在病毒基因阵列和病毒表征实验方面的专业知识来回答这些问题。如果我们证明 HCMV 感染在恶性神经胶质瘤的病因和/或进展中发挥作用，那么我们对这种疾病理解的范式转变将导致 GBM 的新治疗甚至预防药物的出现。 公共健康相关性：恶性神经胶质瘤的病因不明，是最常见的原发性脑肿瘤，每年约有 20,000 名美国人被诊断出，五年内几乎 100% 致命。我们发现，一种常见的人类病毒巨细胞病毒 (CMV) 专门存在于几乎 100% 的这些肿瘤中，我们假设 CMV 可能通过表达驱动恶性肿瘤的基因来引起和/或促进这些肿瘤的生长。我们计划了几项实验，使我们能够确定 CMV 是否在恶性神经胶质瘤生物学中发挥作用，这一发现将对我们对这种癌症的理解产生重大影响，并带来基于抗病毒方法的全新疗法和预防策略。