Cytomegalovirus Gene Expression and Strain Variability in Glioma Pathogenesis

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人恶性脑癌中最常见和最具侵袭性的一种，五年内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。在2002年，我们发现，人巨细胞病毒（HCMV）感染发生在超过90%的GBM。HCMV是先天性脑感染的最常见原因，并且编码使细胞周期、凋亡、增殖、免疫应答、血管生成和细胞侵袭失调的基因产物。我们证明了必需HCMV IE 1基因的表达可以促进原代GBM细胞的增殖（Cobbs et. Can Res，2008），并且感染需要PDGFR 1（一种与胶质瘤发生有关的生长因子受体）的活化（Soroceanu et al.，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CD 133+干细胞样库中，并诱导维持癌症干细胞表型的基因。基于这些证据，我们假设HCMV在GBM发病机制的启动和促进中起作用。我们将集中在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，它们是否促进胶质瘤发病？2)HCMV感染是否诱导肿瘤形成或促进胶质细胞系未感染细胞的胶质瘤表型？和3）“致癌”HCMV株在体内存在于GBM细胞中吗？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合作者的病毒基因阵列和病毒表征实验的专业知识来回答这些问题。如果我们证明HCMV感染在恶性胶质瘤的病因学和/或进展中起作用，那么我们对这种疾病的理解的这种范式转变将导致新的GBM治疗剂甚至预防剂。 公共卫生相关性： 恶性神经胶质瘤是最常见的原发性脑肿瘤，没有已知的原因，每年约有20，000名美国人被诊断出，并且在五年内几乎100%致命。我们已经发现，一种常见的人类病毒，巨细胞病毒（CMV），是专门发现在几乎100%的这些肿瘤，我们假设，CMV可能会导致和/或促进这些肿瘤的生长，通过表达基因驱动恶性肿瘤。我们已经计划了几个实验，这将使我们能够确定CMV是否在恶性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，并导致基于抗病毒方法的全新疗法和预防策略。

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.