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，在五年内有97%的患者死亡。50年来，在确定病因或改善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GBMs中。HCMV是先天性脑感染的最常见原因，其编码的基因产物可调节细胞周期、凋亡、增殖、免疫反应、血管生成和细胞入侵。我们证明了必需的HCMV IE1基因的表达可以促进原代GBM细胞的增殖（Cobbs et. al. can Res, 2008）， PDGFR1（一种与胶质瘤形成有关的生长因子受体）的激活是感染所必需的（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CD133+干细胞样GBM细胞池中，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。我们将关注三个基本问题来验证我们的假设：1)哪些HCMV基因在GBM体内表达，它们是否促进胶质瘤的发病？2) HCMV感染是否在未感染的神经胶质谱系细胞中诱导肿瘤形成或促进胶质瘤表型？3)“致癌”的HCMV毒株是否在GBM细胞中发生？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感染在恶性胶质瘤的病因学和/或进展中起作用，我们对这种疾病的理解的范式转变将导致GBM的新型治疗甚至预防药物。

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.