Genetic Dissection of Glioblastoma: Cell of Origin

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤类型，是一种侵袭性，高度侵袭性和神经破坏性的肿瘤，被认为是所有人类癌症中最致命的肿瘤之一。虽然已知GBM是神经胶质细胞起源的肿瘤，但围绕它们是来自分化的星形胶质细胞、固定的星形胶质细胞祖细胞还是未分化的神经干细胞（NSC），一直存在激烈的争论。成人大脑中NSC的鉴定刺激了人们的猜测，即低分化的GBM可能是由NSC或早期胶质祖细胞的转化引起的，而不是成熟星形胶质细胞的进行性去分化。在这些可能性之间的区别可能是重要的，以预测可能的遗传靶标参与恶性转化和肿瘤进展。事实上，神经胶质细胞分化的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一个重要因素。沿着这些路线，NSC和星形胶质细胞之间可能存在根本性的差异，即每个细胞室达到恶性转化的遗传变化的关键癌症阈值所需的突变数量和类型。本研究的主要目的是验证神经干细胞和终末分化星形胶质细胞均对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，这些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NSC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，并对人类原发性GBM肿瘤进行类似的分析。我们预计，这些信息将为GBM肿瘤细胞及其在大脑中的正常细胞对应体提供必要的见解，并且这些信息将对生成准确、忠实的疾病小鼠模型至关重要。

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.