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（申请人提供）：多形性胶质母细胞瘤（GBM）是最常见、最具破坏性的颅内恶性肿瘤，占所有原发性脑肿瘤的20%，中位生存率仅为14个月。癌细胞通常播散到远离原发肿瘤的地方，并且单个神经胶质瘤细胞从肉眼肿瘤迁移到周围的实质，使得完全手术切除几乎不可能。尽管手术、化疗和放疗取得了进步，但恶性神经胶质瘤的这种迁移能力对任何潜在的治疗都是最大的挑战，并且剩余侵袭性细胞的生长导致99%的复发率。到底是什么调节了脑肿瘤细胞的迁移能力尚不完全清楚，需要研究。该提案的主要目标是了解已知的前迁移信号（例如表皮生长因子（EGF）和 Slit 蛋白）与细胞体积调节之间的联系。 EGF 和 Slit 蛋白可能通过 Akt 途径调节 GBM 干细胞的侵袭和迁移能力，进而调节离子共转运 NKCC1 的激活。我们建议使用各种细胞迁移测定并测量细胞内阴离子浓度来研究导致迁移细胞的主导过程延长的侵袭模式和细胞体积变化。这项工作获得的结果将帮助我们了解参与脑肿瘤细胞迁移级联机制激活的下游信号通路。此外，这些知识无疑将为这种毁灭性疾病的当前次优治疗带来更好的治疗替代方案。