TUMOR SUPPRESSION IN GLIOBLASTOMA MULTIFORME

星形细胞瘤是人类最常见的脑瘤，通常进展 经过恶性程度增加到多形性胶质母细胞瘤(GBM)的阶段， 这种疾病不治之症的终末期。失去起作用的基因 正常情况下抑制细胞增殖(肿瘤抑制基因)定义 星形细胞瘤进展的关键步骤。事实上，删除的副本 在GBM中经常观察到的10号染色体支持这一假说 位于10号染色体上的一个或多个肿瘤抑制基因 中枢神经系统内的关键生长控制检查点。这个 这里概述的研究计划的长期目标是确定 这样的基因。识别候选基因的进展受阻 由于关于染色体的精确位置的不确定性 抑制子基因。原发基底膜肿瘤中的缺失映射涉及 10q24-10qter区域可能是基因的一个位点。一种移位 人GBM细胞系JBSA中的断裂点表明10q22区域 是另一个地点。现在的中心问题是10q的区域是什么 含有能够抑制胶质母细胞瘤细胞生长的基因？ 需要一种功能分析来检测肿瘤细胞的10q片段。 在可以采用分子克隆策略之前抑制生长 有效地分离候选基因。在这项研究提案中， 将使用微细胞融合技术将10q24-10qter和 从正常染色体到JBSA胶质母细胞瘤细胞的10q11-10qter区域 以确定是一个区域还是两个区域抑制肿瘤细胞生长。 然后，肿瘤抑制活性将被追踪到亚微观区域 使用减少辐射策略的10q。与这些同时进行的 GBM患者肿瘤抑制、缺失定位的功能分析 将继续使用新的10号染色体标记以定义 10号染色体的区域小到足以进行候选分子克隆 基因。分离GBM基因将促进我们对细胞的了解 神经系统中的生长控制，并可能为基因提供靶点 星形细胞瘤的未来治疗。

Astrocytoma, the most common brain tumor in humans, typically progresses through stages of increasing malignancy to glioblastoma multiforme (GBM), an incurable, end-stage of the disease. Loss of genes that function normally to suppress cell proliferation (tumor suppressor genes) define critical steps in astrocytoma progression. The fact that deleted copies of chromosome 10 are frequently observed in GBM supports the hypothesis that one or more tumor suppressor genes located on chromosome 10 occupy crucial growth control checkpoints within the central nervous system. The long-range objective of the research program outlined here is to identify such a gene. Progress toward identifying candidate genes has been impeded by uncertainty regarding the precise chromosomal location of the suppressor locus. Deletion mapping in primary GBM tumors implicates the 10q24-10qter region as one possible site for a gene. A translocation breakpoint in a human GBM cell line, JBSA, suggests that the 10q22 region is another site. The central question now is what are the regions of 10q that contain genes capable of suppressing growth in glioblastoma cells? A functional assay is needed to test fragments of 10q for tumor cell growth suppression before molecular cloning strategies can be employed effectively to isolate candidate genes. In this research proposal, microcell fusion techniques will be used to transfer the 10q24-10qter and 10q11-10qter regions from a normal chromosome into JBSA glioblastoma cells to determine whether one or both regions suppress tumor cell growth. Tumor suppressing activity will then be tracked to a submicroscopic region of 10q using a radiation reduction strategy. In parallel with these functional assays for tumor suppression, deletion mapping in GBM patients will be continued using new chromosome 10 markers in order to define a region of chromosome 10 small enough for molecular cloning of candidate genes. Isolation of the GBM gene will advance our knowledge of cell growth control in the nervous system and may provide a target for gene therapy of astrocytomas in the future.