Genetic Pathways of Glioma Invasion

描述：(改编自调查人员的摘要)入侵大脑 实质是胶质细胞恶性表型的固有特征 肿瘤。候选侵袭基因清单包括整合素、基质 重塑酶(蛋白水解酶)和其他细胞运动的介体，如 SPARC和BEHAB，它们都是已知的支持 胎儿细胞、正常成熟细胞以及肿瘤的迁移或侵袭 细胞。虽然预计胶质瘤的侵袭会利用一些正常的 脑侵袭特有的遗传、分子病理学转化为 已澄清。到目前为止，我们在激光捕获显微解剖胶质瘤方面取得了成功 肿瘤核心和侵袭边缘细胞的mRNA差异显示 使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。干扰了 这些基因的表达或基因产物的功能很可能 专门针对侵袭性胶质瘤细胞，因此影响了一个主要的 肿瘤复发的来源。这一假设将通过追求 以下具体目标：1.持续发现表达的候选基因 与非侵袭性细胞相比，在高侵袭性胶质瘤细胞中或沉默 同样的肿瘤。我们将使用激光捕获显微解剖从 人脑胶质瘤标本的冰冻切片，包括侵袭细胞和 肿瘤核心(非侵袭性)，然后使用差异显示来识别 在这些细胞群体中唯一表达的基因。2.临床测试 这些基因在人脑胶质瘤侵袭中的有效性。临床协会 胶质瘤侵袭性和候选基因之间的关系将通过LCM收集 从肿瘤核心和侵袭边缘活检的胶质瘤细胞，以及随后的 从差异中确定候选基因的定量RT-PCR 展示。3.确定其细胞和生化作用机制。 这些基因。特定的抑制或激活策略(抗体， 反义寡核苷酸、已识别基因的转染和定点定向 突变)，并通过共聚焦显微镜进行免疫定位， 与受体和信号分子的免疫共沉淀将用于 确定这些基因在脑胶质瘤侵袭中的作用。一种改进的 了解恶性胶质瘤侵袭的遗传机制 提供了关于这两种疾病的分子病理学的更全面的曲目 胶质瘤发生和胶质瘤进展，以及确定新的靶点 治疗性干预。

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.