Genetic Dissection of Glioblastoma: Cell of Origin

描述(申请人提供)：胶质母细胞瘤(GBM)是最常见的原发脑肿瘤类型，是一种侵袭性、高侵袭性和神经破坏性的肿瘤，被认为是人类所有癌症中最致命的肿瘤之一。虽然已经知道GBM是神经胶质起源的肿瘤，但围绕它们是否起源于分化的星形胶质细胞、承诺的星形胶质细胞前体细胞或未分化的神经干细胞(NSC)，仍存在持续而激烈的争论。在成人脑中发现神经干细胞，刺激了人们的猜测，低分化的GBM可能是由于NSC或早期神经胶质前体细胞的转化，而不是成熟星形胶质细胞的渐进性去分化。在预测恶性转化和肿瘤进展中可能涉及的基因靶点方面，区分这些可能性可能是重要的。事实上，神经胶质细胞的分化状态可能是决定一个给定的基因突变是否充分发挥其致癌潜力的重要因素。沿着这些思路，NSC和星形胶质细胞之间可能存在根本性的差异，因为每个细胞室需要突变的数量和类型才能达到恶性转化的基因变化的临界癌症阈值。这一建议的主要目的是验证神经干细胞和终末分化的星形胶质细胞对GBM相关突变的恶性转化敏感的假设。为了验证这一假设，我们将使用新一代转基因小鼠，这种小鼠可以暂时控制针对NSC或星形胶质细胞的单个或多个突变，并允许随着肿瘤的进展追踪转化细胞的后代。我们将对小鼠神经干细胞和星形胶质细胞来源的肿瘤进行详细的组织学、免疫组织化学和分子分析，以及对原发的人类GBM肿瘤进行类似的分析。我们预计，这些信息将提供对脑内GBM肿瘤细胞和它们的正常细胞对应物的基本洞察，并且这些信息将对建立准确、可靠的疾病小鼠模型至关重要。 与公共卫生相关：基底细胞瘤是人类常见的恶性肿瘤中最致命的。这些研究的结果可以用来开发新的GBM癌症筛查测试、新的诊断辅助工具、新的预后预测指标，并可能有助于确定新的化疗和治疗靶点。

DESCRIPTION (provided by applicant): Glioblastoma (GBM), the most common type of primary brain tumor, is an aggressive, highly invasive and neurologically destructive tumor considered to be among the deadliest of all human cancers. While it is known that GBM are tumors of glial origin, a continuing and intense debate surrounds whether they arise from differentiated astrocytes, committed astrocyte progenitors or undifferentiated neural stem cells (NSC). The identification of NSC in adult brain has stimulated speculation that poorly differentiated GBM may result from transformation of a NSC or early glial progenitor, rather than progressive dedifferentiation of a mature astrocyte. Distinction among these possibilities may be important in predicting the probable genetic targets involved in malignant transformation and tumor progression. Indeed, the state of glial cell differentiation may be an important factor that governs whether a given genetic mutation exerts its full oncogenic potential. Along these lines, it is possible that there may exist fundamental differences between NSC and astrocytes with regard to the number and types of mutations needed for each cellular compartment to reach a critical cancer threshold of genetic changes for malignant transformation. The major goal of this proposal is to test the hypothesis that both the neural stem cells and terminally differentiated astrocytes are sensitive to malignant transformation by GBM relevant mutations. To test this hypothesis we will use a new generation of transgenic mice which permit temporal control over targeting single or multiple mutations specifically to either NSC or astrocytes and allow the progeny of transformed cells to be traced over time as the tumor progresses. We will perform detailed histological, immunohistochemical and molecular analysis of mouse NSC and astrocyte derived tumors as well as similar analysis of primary human GBM tumors. We anticipate that this information will provide essential insight into GBM tumor cells and their normal cellular counterparts in the brain and that this information will be crucial for generating accurate, faithful mouse models of the disease. PUBLIC HEALTH RELEVANCE: GBM is the deadliest of common human malignancies. The results of these studies could be used to develop new screening tests for GBM cancer, new diagnostic aids, new predictors of outcome and may help identify new targets for chemotherapy and treatment.