Complement activation promotes CD133+ glioma cell proliferation

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人最恶性和最常见的原发脑肿瘤。尽管尽一切努力使用多学科方法(如手术、放射和化疗)来治疗这种疾病，但复发是不可避免的，结果很差。基底膜的病理生理学机制仍不完全清楚，尤其是关于胶质瘤细胞的哪些特征有助于局部复发，我们知之甚少。有趣的是，已经发现基底膜中有一小部分细胞能够在低细胞数下引发脑瘤。这些脑肿瘤启动细胞被认为参与了肿瘤的进展，对辅助治疗的抵抗，甚至可能是这些肿瘤的起源细胞。更好地了解这种启动肿瘤的细胞群体的生物学可能会导致针对这些肿瘤中最有问题的细胞群体的新疗法。PARSA实验室正在进行的工作首次发现补体途径，传统上被认为是细胞破坏和免疫的中介，可能参与GBM细胞的增殖。本研究的目的是研究补体成分C3的激活对人脑基底膜肿瘤起始细胞的影响。使用手术患者的胶质瘤，我们计划研究由标记CD133定义的脑肿瘤启动细胞群。我们将在肿瘤生长和侵袭的背景下分析C3激活、C3a生成和C3a受体激活对CD133+细胞的影响。考虑到临床级别的补体抑制剂的可用性，补体途径在GBM进展中的潜在作用对新的治疗方法具有翻译上的好处。 公共卫生相关性：基底节细胞瘤是一种高度侵袭性的肿瘤，会导致神经损伤和死亡的快速进展。在治疗过程中，患者在身体上、情感上和经济上都会感受到巨大的负担。鉴于普遍缺乏有效的辅助治疗，有必要探索新的治疗靶点，以开发新的治疗策略来治疗GBM的增殖和防止复发。我们假设，一种新的肿瘤进展途径，即补体系统，推动了GBM的增殖和侵袭潜力，对这些机制的更好理解可能会导致新的治疗方式。实现这一建议的目标将为胶质瘤患者的新型辅助治疗提供科学基础。

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.