Specialized Niches for Pediatric Astrocytoma Cells

儿童星形细胞瘤细胞的专门利基

• 批准号: 8044511
• 负责人: ROSALIND A. SEGAL
• 金额: $ 35.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-16 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044511
• 关键词: Adenylate Cyclase; Antibodies; Area; Astrocytoma; BRAF gene; Biological Assay; Brain; Brain Stem; Brain region; Cell Survival; Cells; Cerebellar Astrocytoma; Cerebellar Pilocytic Astrocytoma; Cerebellum; Characteristics; Child; Childhood Astrocytic Tumor; Childhood Brain Neoplasm; Cilia; Environment; Event; Exhibits; Future; Growth; Human; Instruction; Location; Maintenance; Mutation; Oncogenic; Organelles; Pathology; Pathway interactions; Patients; Prosencephalon; Sampling; Signal Transduction; Slice; Specificity; Specimen; Therapeutic; Treatment Efficacy; Tubulin; Xenograft procedure; base; hindbrain; innovation; migration; neoplastic cell; nerve stem cell; new therapeutic target; novel therapeutic intervention; overexpression; response; tumor; tumor growth

The overall objective ofthis project is to develop a new understanding ofthe microenvironment that supports the growth, survival and migration of astrocytoma cells, and thereby identify new therapeutic approaches. In preliminary studies we have shown that human astrocytoma cells do not grow indiscriminately within the brain parenchyma, but prefer to grow in particular microenvironments. In the proposed studies we will use primary cultures from patient samples to determine whether astrocytomas are addicted to the environment of the brain region in which they developed, and to define cellular mechanisms by which the tumor microenvironment promotes tumor maintenance. We have three aims: Aim One: Determine whether pediatric astrocytomas are "addicted" to the particular location in which they originated. We will use a new slice overiay assay, to determine whether i) forebrain tumors preferenfially grow in the specialized microenvironment of the forebrain; ii) hindbrain tumors preferentially grow in the cerebellum and brainstem areas ofthe hindbrain; iii) BRAF overexpression, a characteristic feature of cerebellar pilocytic astrocytomas, specifically facilitates growth of neural precursor in the cerebellar microenvironment. Aim Two: Define the cellular basis ofthe microenvironment While the microenvironment is cleariy important for tumor growth and maintenance, the reason why tumor cells are preferentially found in particular locations is not understood. We will determine whether i) the microenvironment stimulates tumor proliferafion; ii) the microenvironment selectively promotes tumor cell survival; iii) tumor cells preferentially migrate towards this microenvironment. Aim Three: Determine whether primary cilia coordinate the tumor cell response to its microenvironment. Our preliminary studies indicate that many astrocytoma samples exhibit primary cilia, visualized with antibodies to acetylated tubulin or adenylate cyclase 3. To determine whether primary cilia are signaling organelles that contribute to growth of astrocytomas, we will determine whether i) Primary cilia are preferenfially found on higher grade tumors; ii) Primary cilia point towards the vasculature; iii) components of crifical growth pathways localized to cilia of tumor cells; iv) Primary cilia are required for tumor growth. RELEVANCE (See instructions): In cooperation with the Innovative Neuro Pathology (INP) Core and Projects One and Two, these studies on the tumor microenvironment will identify new therapeutic targets for treating pediatric brain tumors. Future therapies can then be developed that attack the interactions of the tumor and its microenvironment, an approach that may allow therapeutic efficacy with less damage to the normally developing brains of children. J PROJECT/

本项目的总体目标是对微环境有一个新的理解， 星形细胞瘤细胞的生长、存活和迁移，从而确定新的治疗方法。在 我们的初步研究表明，人星形细胞瘤细胞不会在肿瘤细胞内不加选择地生长， 脑实质，但更喜欢在特定的微环境中生长。在拟议的研究中，我们将使用 从患者样本中进行原代培养，以确定星形细胞瘤是否依赖于 他们发展的大脑区域，并确定肿瘤发生的细胞机制。 微环境促进肿瘤维持。我们有三个目标： 目的一：确定儿童星形细胞瘤是否对肿瘤的特定部位“上瘾”。 他们所创造的。我们将使用一种新的切片检测方法来确定i）前脑肿瘤 优先生长在前脑的特殊微环境中; ii）后脑肿瘤优先 生长在小脑和脑干区域的后脑; iii）BRAF过表达，一个特征性的 小脑毛细胞星形细胞瘤的特征，特别是促进小脑神经前体细胞的生长 微环境 目的二：明确微环境的细胞基础 对于肿瘤的生长和维持很重要，肿瘤细胞被优先发现的原因特别是 位置不了解。我们将确定i）微环境是否刺激肿瘤 ii）微环境选择性地促进肿瘤细胞存活; iii）肿瘤细胞优先地 向这个微环境迁移。 目的三：确定初级纤毛是否协调肿瘤细胞对其纤毛的反应。 微环境我们的初步研究表明，许多星形细胞瘤样本显示初级纤毛， 用乙酰化微管蛋白或腺苷酸环化酶3的抗体显示。为了确定初级纤毛 是有助于星形细胞瘤生长的信号细胞器，我们将确定i）初级纤毛 优先发现于更高级别的肿瘤; ii）初级纤毛指向脉管系统; iii） 关键生长途径的成分定位于肿瘤细胞的纤毛; iv）初级纤毛是肿瘤细胞生长所必需的。 肿瘤生长 相关性（参见说明）： 与创新神经病理学（INP）核心和项目一和二合作，这些研究 肿瘤微环境的研究将确定治疗小儿脑肿瘤的新靶点。未来 然后可以开发出攻击肿瘤及其微环境相互作用的疗法， 这种方法可以在对儿童正常发育的大脑损伤较小的情况下实现治疗效果。 J 项目/