Genetic Pathways of Glioma Invasion

描述：（改编自研究者摘要）侵入大脑 实质是胶质细胞恶性表型的固有特征， 肿瘤。候选侵袭基因的列表包括整合素、基质金属蛋白酶、免疫球蛋白和免疫球蛋白。 重塑酶（蛋白酶）和细胞运动的其他介质， 和SDE B，它们是已知支持 胎儿细胞、正常成熟细胞以及肿瘤的迁移或侵袭 细胞虽然预期胶质瘤侵袭将利用一些正常的 遗传，分子病理学特定的脑入侵转化为 阐明。我们迄今为止成功地用激光捕获显微切割胶质瘤 来自肿瘤核心和浸润边缘的细胞，随后进行mRNA差异显示 我们假设恶性胶质瘤细胞的局部侵袭是由 通过特定和独特的基因表达变化。干扰 这些基因的表达或基因产物的功能可能 特异性靶向侵袭性神经胶质瘤细胞，从而影响主要的 肿瘤复发的来源。这一假设将通过追踪 具体目标：1。支持候选基因表达的发现 与非侵袭性胶质瘤细胞相比， 同样的肿瘤。我们将使用激光捕获显微切割技术从 人类胶质瘤标本的冷冻切片，包括侵袭细胞和来自 肿瘤核心（非侵入性），然后采用差异显示来识别 在这些细胞群中独特表达的基因。2.临床试验 验证这些基因在人脑胶质瘤侵袭中的作用。临床关联 胶质瘤侵袭和候选基因之间的关系将通过LCM收集 从活检的肿瘤核心和侵袭边缘，以及随后的 定量RT-PCR用于从差异中鉴定的候选基因 显示.和3.确定细胞和生化作用机制 这些基因。特异性抑制或激活策略（抗体， 反义寡核苷酸，转染鉴定的基因，和定点 诱变），和通过共聚焦显微镜的免疫定位， 与受体和信号分子的免疫共沉淀将用于 确定这些基因在胶质瘤侵袭中的功能。一种改进 对恶性胶质瘤侵袭的遗传机制的了解将 提供了一个更全面的分子病理学的剧目， 神经胶质瘤发生和神经胶质瘤进展，以及确定新的目标， 治疗干预

DESCRIPTION: (Adapted from the investigator's abstract) Invasion into brain parenchyma is an inherent feature of the malignant phenotype of glial neoplasms. The list of candidate invasion genes includes integrins, matrix remodeling enzymes (proteases), and other mediators of cell motility such as SPARC and BEHAB, which are well-characterized processes known to support migration or invasion of fetal cells, normal mature cells, as well as tumor cells. While it is anticipated that glioma invasion would exploit some normal genetic, molecular pathology specific to brain invasion transformed as been elucidated. Our success to date with laser capture microdissection of glioma cells from tumor core and invasive rim followed by mRNA differential display leads us to HYPOTHESIZE that local invasion by malignant glioma cells is driven by specific and unique gene expression changes. Interference with the expression of these genes or function of the gene products is likely to specifically target invasive glioma cells, consequently impacting a major source of tumor recurrence. This hypothesis will be tested by pursuing the following specific aims: 1. sustain the discovery of candidate genes expressed or silenced in highly invasive glioma cells compared to noninvading cells in the same tumor. We will use laser capture microdissection to retrieve from cryostat sections of human glioma specimens both invading cells and cells from the tumor core (non invading) and then employ differential display to identify genes uniquely expressed in these populations of cells. 2. test for clinical validation of the these genes in human glioma invasion. Clinical associations between glioma invasion and gene candidates will be tested by LCM collection of glioma cells from tumor core and invasive rim of biopsies, and subsequent quantitative RT-PCR for gene candidates identified from the differential display. And 3. determine the cellular and biochemical mechanisms of action of these genes. Specific inhibition or activation strategies (antibodies, antisense oligonucleotides, transfection of identified genes, and site-directed mutagenesis), and immunolocalization by confocal microscopy, co-immunoprecipitation with receptors and signaling molecules will be used to determine the function of the genes in glioma invasion. An improved understanding of genetic mechanisms underlying malignant glioma invasion will provide a more thorough repertoire of the molecular pathology of both gliomagenesis and glioma progression, as well as identify novel targets for therapeutic intervention.