Complement activation promotes CD133+ glioma cell proliferation

补体激活促进 CD133 胶质瘤细胞增殖

• 批准号: 8059447
• 负责人: Michael C Oh
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059447
• 关键词: Adjuvant Therapy; Adult; Animal Model; Area; Behavior; Brain Neoplasms; C3bi; Cell Count; Cell Proliferation; Cells; Cessation of life; Characteristics; Clinical; Complement; Complement 3a; Complement Activation; Complement Inactivators; Data; Deposition; Disease; Evaluation; Excision; Foundations; Functional disorder; Generations; Glioblastoma; Glioma; Goals; Human; Immunity; Impairment; Implant; In Vitro; Laboratories; Lead; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediator of activation protein; Modality; Molecular; Mus; Necrosis; Neoplasms; Neurologic; Nude Mice; Operative Surgical Procedures; Opsonin; Organ; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Population; Primary Brain Neoplasms; Production; Property; Radiation; Radiosurgery; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recurrence; Resected; Resistance; Role; Stem cells; Surface; Testing; Time; Tissues; Tumor Biology; Tumor Cell Invasion; Work; Xenograft Model; cancer stem cell; chemotherapy; complement C3 precursor; complement pathway; complement system; conventional therapy; cytotoxic; experience; glioma cell line; in vivo; inhibitor/antagonist; insight; neoplastic cell; nerve stem cell; new therapeutic target; novel; novel therapeutics; prevent; receptor; small molecule; treatment strategy; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most malignant and common form of primary brain tumor in adults. Despite every effort to treat this disorder using multi-disciplinary approaches (i.e. surgery, radiation, and chemotherapy), recurrence is inevitable with poor outcomes. The pathophysiology of GBM remains incompletely understood, and in particular, little is known regarding what features of glioma cells facilitate local recurrence. Interestingly, a small population of cells in GBM has been identified that are able to initiate brain tumors at low cell numbers. These brain tumor-initiating cells are thought to be involved in tumor progression, resistance to adjuvant therapies, and might even represent the cell of origin for these tumors. A better understanding of the biology of this tumor-initiating cell population could lead to novel therapies targeting the most problematic cell population in these tumors. Ongoing work in the Parsa laboratory has identified for the first time that the complement pathway, traditionally thought to be a mediator of cellular destruction and immunity, may be involved in GBM cell proliferation. The goal of this proposal is to study the impact of complement component C3 activation on the brain tumor-initiating cells in human GBM. Using gliomas resected from patients undergoing surgery, we plan to study a brain tumor-initiating cell population as defined by the marker CD133. We will analyze the impact of C3 activation, C3a generation, and C3a receptor activation on the CD133+ cells within the context of tumor growth and invasion. Given the availability of clinical grade complement inhibitors, a potential role for the complement pathway in GBM progression has translational benefit towards novel therapy. PUBLIC HEALTH RELEVANCE: GBM is a highly aggressive neoplasm which leads to rapid progression of neurologic impairment and death. Patients experience a significant burden physically, emotionally, and financially during the treatment course. Given the general lack of effective adjuvant therapies, exploring novel therapeutic targets is warranted to develop new treatment strategies to treat GBM proliferation and prevent recurrences. We hypothesize that a novel pathway of tumor progression, the complement system, drives GBM proliferation and invasive potential and that a better understanding of these mechanisms may lead to new therapeutic modalities. Achieving the goals of this proposal would provide the scientific foundation for a new type of adjuvant therapy for glioma patients.

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是成人原发性脑肿瘤中最恶性和最常见的形式。尽管竭尽全力使用多学科方法（如手术、放疗和化疗）治疗这种疾病，但复发是不可避免的，预后不佳。GBM的病理生理机制尚不完全清楚，特别是胶质瘤细胞的哪些特征促进了局部复发。有趣的是，在GBM中有一小部分细胞已经被确定能够在低细胞数量下引发脑肿瘤。这些脑肿瘤起始细胞被认为参与肿瘤的进展，对辅助治疗的抵抗，甚至可能代表这些肿瘤的起源细胞。更好地了解这种肿瘤启动细胞群的生物学可能会导致针对这些肿瘤中最具问题的细胞群的新疗法。Parsa实验室正在进行的工作首次确定了补体途径，传统上被认为是细胞破坏和免疫的中介，可能参与GBM细胞增殖。本研究的目的是研究补体成分C3激活对人GBM脑肿瘤启动细胞的影响。利用手术患者切除的胶质瘤，我们计划研究由CD133标记物定义的脑肿瘤启动细胞群。我们将分析C3激活、C3a生成和C3a受体激活对肿瘤生长和侵袭背景下CD133+细胞的影响。鉴于临床级补体抑制剂的可用性，补体途径在GBM进展中的潜在作用具有转化为新疗法的益处。

项目成果

Gross total resection improves overall survival in children with choroid plexus carcinoma.

肉眼全切除可提高脉络丛癌儿童的总生存率。

• DOI: 10.1007/s11060-013-1281-5
• 发表时间: 2014
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Sun,MatthewZ;Ivan,MichaelE;Clark,AaronJ;Oh,MichaelC;Delance,ArthurR;Oh,Taemin;Safaee,Michael;Kaur,Gurvinder;Bloch,Orin;Molinaro,Annette;Gupta,Nalin;Parsa,AndrewT
• 通讯作者: Parsa,AndrewT

Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells.

• DOI: 10.1371/journal.pone.0047846
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Oh MC;Kim JM;Safaee M;Kaur G;Sun MZ;Kaur R;Celli A;Mauro TM;Parsa AT
• 通讯作者: Parsa AT

Prognosis by tumor location in adults with intracranial ependymomas.

• DOI: 10.1016/j.jocn.2014.05.011
• 发表时间: 2014-12
• 期刊: JOURNAL OF CLINICAL NEUROSCIENCE
• 影响因子: 2
• 作者: Sayegh, Eli T.;Aranda, Derick;Kim, Joseph M.;Oh, Taemin;Parsa, Andrew T.;Oh, Michael C.
• 通讯作者: Oh, Michael C.

Spinal ependymomas: benefits of extent of resection for different histological grades.

• DOI: 10.1016/j.jocn.2012.12.010
• 发表时间: 2013-10
• 期刊: JOURNAL OF CLINICAL NEUROSCIENCE
• 影响因子: 2
• 作者: Oh, Michael C.;Tarapore, Phiroz E.;Kim, Joseph M.;Sun, Matthew Z.;Safaee, Michael;Kaur, Gurvinder;Aranda, Derick M.;Parsa, Andrew T.
• 通讯作者: Parsa, Andrew T.