Role of NKCC1 on Brain Tumor Stem Cell Migration After EGF and Slit-2 Stimulation

EGF 和 Slit-2 刺激后 NKCC1 对脑肿瘤干细胞迁移的作用

• 批准号: 8625346
• 负责人: ALFREDO QUINONES-HINOJOSA
• 金额: $ 48.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625346
• 关键词: Accounting; Affect; Anions; Behavior; Brain; Brain Neoplasms; Cell Volumes; Cells; Characteristics; Chloride Ion; Chlorides; Diffuse; Disease; Drosophila sli protein; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Excision; Glioblastoma; Glioma; Goals; Growth; Growth Factor; Human; In Vitro; Incidence; Individual; Infiltration; Ion Cotransport; Knowledge; Link; Malignant Glioma; Malignant Intracranial Neoplasm; Malignant Neoplasms; Measures; Mediating; Methylation; Migration Assay; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Play; Population; Primary Brain Neoplasms; Primary Neoplasm; Process; Quinones; Radiation therapy; Recurrence; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stem cells; Survival Rate; System; Testing; Therapeutic; Tumor Angiogenesis; Tumor Cell Invasion; Tumor Stem Cells; Work; axonal guidance; cancer cell; cell motility; chemotherapy; glioma cell line; in vivo; medulloblastoma; migration; neoplastic cell; nerve stem cell; new therapeutic target; outcome forecast; overexpression; prevent; protein expression; public health relevance; response; sodium-potassium-chloride cotransporter 1 protein; tumor

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and devastating intracranial malignant tumor accounts for 20% of all primary brain tumors and has a median survival rate of only 14 months. Cancer cells often disseminate far from primary tumors and individual glioma cells migrate from the gross tumor into the surrounding parenchyma, making complete surgical resection nearly impossible. This migratory capacity of malignant gliomas represents the greatest challenge to any potential therapy in spite of advances in surgery, chemotherapy and radiotherapy and growth of the remaining invasive cells leads to a recurrence incidence of 99%. What exactly regulates the migratory capacity of brain tumor cells is not fully understood and need to be studied. The main goal of this proposal is to understand the link between known pro- migratory signals such as epidermal growth factor (EGF) and Slit proteins with cell volume regulation. EGF and Slit proteins may play an important role in the modulation of invasive and migratory ability of GBM derived stem cells through Akt pathway that in turn regulates the activation of ion cotransport NKCC1. We propose to study invasive patterns and cell volume changes resulting in the extension of a leading process of a migrating cell, using various cell migration assays and measuring intracellular anion concentration. The results obtained from this work will help us understand the downstream signaling pathways involved in the activation of cascade mechanism responsible for brain tumor cell migration. Further, such knowledge will undoubtedly result in better therapeutic alternatives to current sub-optimal treatments for this devastating disease.

描述（由申请人提供）：多形胶质母细胞瘤（GBM），最常见和毁灭性的颅内恶性肿瘤占所有原发性脑肿瘤的20％，中位存活率仅为14个月。癌细胞通常远离原发性肿瘤，单个神经胶质瘤细胞从总肿瘤迁移到周围的实质中，几乎不可能进行完全的手术切除。尽管手术，化学疗法和放疗以及剩余的侵袭性细胞的生长，这种恶性神经瘤的迁徙能力是对任何潜在疗法的最大挑战，导致复发率为99％。尚未完全了解脑肿瘤细胞的迁移能力的准确调节和需要研究。该提案的主要目的是了解已知的迁移信号（例如表皮生长因子（EGF））和带细胞体积调节的SLIT蛋白之间的联系。 EGF和SLIT蛋白可能在通过AKT途径的GBM衍生干细胞的侵入性和迁移能力的调节中起重要作用，这反过来又调节了离子Cotransport NKCC1的激活。我们建议研究侵入性模式和细胞体积变化，从而使用各种细胞迁移测定并测量细胞内阴离子浓度，从而扩展迁移细胞的主要过程。从这项工作中获得的结果将有助于我们了解导致脑肿瘤细胞迁移的级联机制激活的下游信号传导途径。此外，这种知识无疑将为这种毁灭性疾病提供当前优化治疗的更好的治疗替代方法。