TUMOR SUPPRESSION IN GLIOBLASTOMA MULTIFORME

点击翻译按钮获取中文摘要

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.