MECHANISM OF INDUCTION OF MALIGNANT GLIOMAS

恶性胶质瘤的诱发机制

• 批准号: 6194768
• 负责人: DEMETRIUS Michael KOKKINAKIS
• 金额: $ 21.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194768
• 关键词: astrocytes; athymic mouse; cell differentiation; cell migration; cell proliferation; chemical carcinogenesis; cyclin dependent kinase; epidermal growth factor; gene deletion mutation; gene mutation; gene rearrangement; glioma; growth factor receptors; laboratory rat; methylnitrosourea; natural gene amplification; neoplasm /cancer genetics; neoplastic process; oligodendroglia; p53 gene /protein; platelet derived growth factor; tissue /cell culture; tumor suppressor genes

Presently, the management of gliomas consists principally of surgical resection and radiation that are effective in reducing tumor burden, but are usually not curative. The limitations of surgery and radiation are clearly related to the ability of glioma cells to infiltrate intact parenchyma, apparently, via migration from the tumor site. Thus, the development of therapies to target tumor cells within normal tissue without damaging functional neurons has considerable merit. The main obstacle to the development of such therapies is our lack of understanding of the infiltrating cell. The chemotherapeutic target in gliomas must include not only residual tumor cells left behind by surgery and radiation, but also the infiltrating cells that may be protected by an intact brain barrier and low mitotic activity thus making radiotherapy and chemotherapy less effective. Recent advances in brain tumor cell biology have given rise to the hypothesis that the cell of origin of glial tumors could be a mutated "progenitor" of glial cells which upon certain conditions gives rise to astrocytic and oligodendroglial tumors. This view is supported by the isolation of normal "progenitor" cells and the observation that most glial tumors are mixed, containing both astrocytic and oligodendrocytic components. It is further hypothesized that glioma cells may mimic their cells of origin by maintaining their migratory ability. In order to test this hypothesis the applicant has introduced the adult rat model which develops true glial tumors upon continuous exposure to N-methylnitrosourea (MNU). Multipotent progenitor cells from rats that can differentiate into either astrocytic or oligodendroglial like cells have been isolated and studied. The applicant has also isolated cells from the apparently normal brain parenchyma of MNU treated tumor free rats. These mutant cells can migrate, and differentiate into oligodendroglial or astrocytic morphologies upon stimulation with growth factors; they have some potential to induce tumors in athymic mice. Karyotyping of mutated progenitor (multipotent) cells shows various degrees of chromosomal abnormalities that correlate well with their respective tumorigenic potential. The applicant's aim is to characterize migrating gliomal cells from seemingly normal brain tissue before the development of MNU induced tumors and compare them with frank tumor cells infiltrating the eloquent parenchyma according to their potential to proliferate, transform into oligodendroglial and astrocytic morphology, expression of antigens and tumorigenic potency. Determination of genetic differences between tumorigenic and non-tumorigenic progenitor cells will be helpful in determining the mechanism(s) of glial tumor development. Genetic differences between tumor cells and those capable of infiltrating the normal parenchyma will also be identified and compared to those of initiated multipotent progenitor cells in order to understand their lineage.

目前，神经胶质瘤的治疗主要包括手术治疗 切除和放疗可有效减轻肿瘤负荷， 但通常没有疗效。手术和放射的局限性是 与神经胶质瘤细胞浸润完整实质的能力明显相关， 显然，通过从肿瘤部位迁移。因此，发展 靶向正常组织内肿瘤细胞而不损伤肿瘤细胞的疗法 功能神经元具有相当大的优点。发展的主要障碍 此类疗法的缺点是我们缺乏对浸润细胞的了解。这 胶质瘤的化疗靶点必须不仅包括残留的肿瘤细胞 手术和放疗留下的，还有可能的浸润细胞 受到完整的脑屏障和低有丝分裂活性的保护，从而使 放疗和化疗效果较差。脑肿瘤的最新进展 细胞生物学提出了这样的假说：胶质细胞的起源细胞 肿瘤可能是神经胶质细胞的突变“祖细胞”，在某些情况下 条件会引起星形细胞肿瘤和少突胶质细胞肿瘤。这个视图是 正常“祖”细胞的分离和观察结果支持 大多数神经胶质瘤是混合性的，同时含有星形细胞和 少突胶质细胞成分。进一步假设神经胶质瘤细胞可能 通过保持其迁移能力来模仿其起源细胞。为了 检验这一假设申请人引入了成年大鼠模型 持续接触 N-甲基亚硝基脲会形成真正的神经胶质瘤 （MNU）。来自大鼠的多能祖细胞可以分化为 星形胶质细胞或少突胶质细胞样细胞已被分离并 研究过。申请人还从表面正常的大脑中分离出细胞 MNU 治疗的无肿瘤大鼠的实质。这些突变细胞可以迁移，并且 刺激后分化为少突胶质细胞或星形胶质细胞形态 含有生长因子；它们有可能在无胸腺小鼠中诱发肿瘤。 突变祖细胞（多能）的核型分析显示出不同程度的 与其各自的致瘤性密切相关的染色体异常 潜在的。申请人的目的是表征从 在 MNU 诱发肿瘤发生之前看似正常的脑组织 将它们与浸润雄辩实质的坦率肿瘤细胞进行比较 根据其增殖潜力，转化为少突胶质细胞 以及星形细胞形态、抗原表达和致瘤能力。 确定致瘤性和非致瘤性之间的遗传差异 祖细胞将有助于确定神经胶质瘤的机制 发展。肿瘤细胞和具有能力的细胞之间的遗传差异 渗透正常实质也将被识别并与 那些启动的多能祖细胞，以便了解它们的 血统。