The Role of PDGFR in Medulloblastoma Progression

PDGFR 在髓母细胞瘤进展中的作用

• 批准号: 7413327
• 负责人: TOBEY J. MACDONALD
• 金额: $ 25.75万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413327
• 关键词: Adhesions; Affect; Apoptosis; Biological Process; Blocking Antibodies; Brain; Cell Line; Cell Proliferation Regulation; Cell Surface Receptors; Cells; Child; Clinical; Commit; Computer Simulation; Cranial Irradiation; Data; Data Set; Development; Disease; Dose; Environment; Gene Expression; Genes; Goals; Growth; Growth Factor; Human; In Vitro; Infant; Malignant - descriptor; Malignant neoplasm of brain; Mitogen-Activated Protein Kinases; Molecular; Morbidity - disease rate; Multipotent Stem Cells; Neoplasm Metastasis; Neural Crest; Neuraxis; Neurologic; Neurons; Numbers; Outcome; PDGF receptor tyrosine kinase; PDGFRA gene; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Platelet Inhibitors; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Protein Overexpression; Proteins; RNA; RNA Interference; Receptor Mediated Signal Transduction; Receptor Signaling; Regulation; Reporting; Research; Research Personnel; Role; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Stimulus; Structure; Survival Rate; Survivors; Testing; Therapeutic; Therapeutic Intervention; Thinking; Transfection; Tumor Biology; autocrine; base; cell growth; cell motility; design; experience; in vivo; inhibitor/antagonist; mRNA Expression; medulloblastoma; migration; neoplastic cell; novel; novel therapeutics; outcome forecast; paracrine; precursor cell; prevent; protein activation; protein expression; receptor; receptor expression; response; tumor

Medulloblastoma is the most common malignant brain tumor in children. To approach the problem of effective therapy, the progression of human medulloblastoma must first be understood. We hypothesize that )latelet-derived growth factor (PDGFR)-mediated signal transduction enhances tumor cell responses that promote the growth and metastatic spread of medulloblastoma, and have shown that (i) PDGFR is significantly overexpressed by metastatic medulloblastomas, (ii)inhibitors of medulloblastoma cell PDGFR activity decrease phosphorylation of the downstream signaling target, MAPK, alter gene expression, and decrease cell migration and survival and (iii) in silico analysis of 135 known pro-metastatic genes within ndependent datasets of microarraygene expression of medulloblastomas, only three genes, including DDGFR, demonstrated detectable mRNA expression in at least one third of all tumors analyzed and significant overexpression by metastatic tumors in each dataset. These data, combined with the preliminary data showing that both alpha (PDGFRA) and beta (PDGFRB) subtypes of the receptor are 1) expressed on the RNA and protein level by medulloblastoma tumors and cells, 2) sparsely expressed by normal brain, 3) activated in an autocrine and paracrine fashion in medulloblastoma cells, and 4) capable of inducing apoptosis of medulloblastoma cells in a dose-dependent manner following treatment with a selective inhibitor of PDGFR tyrosine kinase activity, suggest a mechanism by which PDGFR may be vital for medulloblastoma growth and progression. Thus, PDGFR is a potential novel target for therapeutic intervention. To test this hypothesis we will employ human medulloblastoma cell lines. We will (i) conduct comprehensive in vitro studies to determine the PDGFR signaling cascade and its effects on survival, proliferation, adhesion, migration and invasion, (ii) determine the key gene expression changes induced by PDGFR signaling in these cells, (iii) develop medulloblastoma cells with deficient PDGFR expression by inducible siRNA transfection specific for each PDGFR and determine the effect of inhibited expression and activity on survival, proliferation and migration in vitro and growth and metastasis in vivo, and (iv) determine the expression pattern of phbsphorylated PDGFR protein and its correlation with metastasis and outcome in human medulloblastomas as a way to assessthe potential clinical utility of PDGFR inhibitors for this disease

髓母细胞瘤是儿童最常见的恶性脑肿瘤。探讨…问题 有效的治疗，人髓母细胞瘤的进展必须首先了解。我们假设 ）迟发性衍生生长因子（PDGFR）介导的信号转导增强肿瘤细胞应答， 促进成神经管细胞瘤的生长和转移扩散，并已显示（i）PDGFR是 由转移性髓母细胞瘤显著过表达，（ii）髓母细胞瘤细胞PDGFR的抑制剂 活性降低下游信号传导靶标MAPK的磷酸化，改变基因表达，和 减少细胞迁移和存活，和（iii）在计算机上分析135个已知的促转移基因， 神经管母细胞瘤基因表达的非依赖性数据集，只有三个基因，包括 DDGFR在至少三分之一的分析肿瘤中表现出可检测的mRNA表达， 在每个数据集中转移性肿瘤的显著过表达。这些数据与初步的 数据显示，受体的α（PDGFRA）和β（PDGFRB）亚型均1）表达于 成神经管细胞瘤肿瘤和细胞的RNA和蛋白质水平，2）正常脑稀疏表达，3） 在髓母细胞瘤细胞中以自分泌和旁分泌方式激活，和4）能够诱导 用选择性抑制剂处理后髓母细胞瘤细胞以剂量依赖性方式凋亡 PDGFR酪氨酸激酶活性，提示PDGFR可能对髓母细胞瘤至关重要的机制 成长和进步。因此，PDGFR是治疗干预的潜在新靶点。为了验证这一 假设我们将使用人髓母细胞瘤细胞系。我们将（i）进行全面的体外试验 确定PDGFR信号级联及其对存活、增殖、粘附 迁移和入侵，（ii）确定PDGFR信号传导诱导的关键基因表达变化 这些细胞，（iii）通过诱导型siRNA产生PDGFR表达缺陷的髓母细胞瘤细胞 转染特异性的每一个PDGFR，并确定抑制的表达和活性的影响， 体外存活、增殖和迁移以及体内生长和转移，以及（iv）确定 磷酸化PDGFR蛋白表达模式及其与肺癌转移和预后的关系 人髓母细胞瘤作为评估PDGFR抑制剂对这种疾病的潜在临床效用的一种方法