Cytomegalovirus Gene Expression and Strain Variability in Glioma Pathogenesis

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人恶性脑癌中最常见和最具侵袭性的形式，在五年内导致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90%以上的巨细胞瘤中。巨细胞病毒是先天性脑感染最常见的原因，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。我们证明了必要的HCMV IE1基因的表达可以促进原代GBM细胞(Cobbs et.艾尔Can Res，2008)，而参与胶质瘤形成的生长因子受体PDGFR1的激活是感染所必需的(Sorocanu等人，自然，2008)。我们最近的初步数据表明，HCMV感染优先发生在体内CD133+的GBM干细胞池中，并诱导维持肿瘤干细胞表型的基因。根据这一证据，我们推测HCMV在GBM的发病机制中起着启动和促进作用。我们将集中于三个基本问题来验证我们的假设：1)哪些HCMV基因在GBM中体内表达，它们是否促进了胶质瘤的发病？2)HCMV感染是否诱导了胶质细胞系未感染细胞的肿瘤形成或促进了胶质瘤的表型？3)GBM细胞中是否存在致癌的HCMV毒株？我们将利用我们的肿瘤组织库、我们广泛的体外和体内脑肿瘤专业知识，以及OHSU和UAB合作者的专业知识来进行病毒基因阵列和病毒特性实验，以回答这些问题。如果我们证明巨细胞病毒感染在恶性胶质瘤的病因和/或进展中起作用，我们对这种疾病的理解的这种范式的转变将导致新的治疗甚至预防基底膜的药物。 公共卫生相关性：恶性胶质瘤是最常见的原发脑瘤，原因不明，每年约有2万名美国人被诊断出恶性胶质瘤，五年内几乎100%死亡。我们发现一种常见的人类病毒，巨细胞病毒(CMV)，在几乎100%的这些肿瘤中被发现，我们假设CMV可能通过表达驱动恶性肿瘤的基因而导致和/或促进这些肿瘤的生长。我们已经计划了几个实验，使我们能够确定CMV是否在恶性胶质瘤生物学中扮演CMV的角色-这一发现将对我们对这种癌症的理解产生重大影响，并导致基于抗病毒方法的全新治疗和预防策略。

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.