MECHANISM OF INDUCTION OF MALIGNANT GLIOMAS

目前，神经胶质瘤的治疗主要包括外科手术， 切除术和放射治疗能有效降低肿瘤负荷， 但通常不能治愈。手术和放疗的局限性在于 与胶质瘤细胞浸润完整实质的能力明显相关， 显然是通过肿瘤部位的转移因此， 靶向正常组织内的肿瘤细胞而不损害 功能性神经元具有相当大的优点。发展的主要障碍 是我们对浸润细胞缺乏了解。的 胶质瘤的化疗靶点不仅包括残留的肿瘤细胞， 手术和放疗留下的，但也有浸润细胞， 受到完整的脑屏障和低有丝分裂活性的保护， 放疗和化疗效果较差。脑肿瘤研究进展 细胞生物学提出了一种假设，即神经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”， 条件引起星形细胞和少突胶质细胞肿瘤。这种观点是 通过分离正常的“祖”细胞和观察 大多数神经胶质瘤是混合性的，既有星形细胞瘤， 少突胶质细胞成分。进一步假设胶质瘤细胞可能 通过保持迁移能力来模仿它们的原始细胞。为了 为了验证这一假设，申请人引入了成年大鼠模型， 在持续暴露于N-甲基亚硝基脲后发生真正的神经胶质瘤 （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经被分离， 研究了申请人还从明显正常的大脑中分离出细胞 MNU治疗的无瘤大鼠的实质。这些突变细胞可以迁移， 在刺激后分化成少突胶质细胞或星形胶质细胞形态 与生长因子;他们有一定的潜力，诱发肿瘤的无胸腺小鼠。 突变的祖细胞（多能）细胞的核型分析显示出不同程度的 染色体异常与它们各自的致瘤性 潜力申请人的目的是表征从胶质瘤中迁移的胶质瘤细胞。 在MNU诱导的肿瘤发展之前看似正常的脑组织， 与浸润功能实质的坦率的肿瘤细胞相比， 根据其增殖、转化为少突胶质细胞的潜力 星形胶质细胞形态、抗原表达和致瘤潜能。 致瘤性和非致瘤性之间遗传差异的确定 祖细胞将有助于确定胶质瘤的机制 发展肿瘤细胞和那些能够 还将识别浸润正常实质的细胞，并与 启动的多能祖细胞，以了解他们的 脉

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.