Crosstalk Between Platelets and Brain Tumor Initiating Cells in Glioblastoma

胶质母细胞瘤中血小板与脑肿瘤起始细胞之间的串扰

• 批准号: 8907582
• 负责人: CHRISTINE H LEE
• 金额: $ 4.31万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907582
• 关键词: Acute; Antibodies; Area; Automobile Driving; Biological; Biological Assay; Blood Circulation; Blood Platelets; Blood Vessels; Brain; Brain Neoplasms; Cell Communication; Cells; Cellular biology; Clinical; Clinical Research; Data; Development; Disease; Environment; Epidermal Growth Factor Receptor; Event; Exhibits; Genetic; Glioblastoma; Growth; Growth Factor Receptors; Heterogeneity; Histologic; Human; Hypoxia; In Vitro; Invaded; Laboratories; Lesion; Location; Mediating; Molecular; Mus; Necrosis; Neoplasm Circulating Cells; Neoplasm Metastasis; Neuraxis; Non-Malignant; Outcome; Patients; Phenotype; Phosphorylation; Platelet Count measurement; Prognostic Marker; RNA; RNA Interference; Recurrence; Resistance; Role; Signal Transduction; Specimen; Stem cells; Testing; Therapeutic; Tumor Burden; base; cancer therapy; cell growth; cell motility; density; design; driving force; improved; in vivo; inhibitor/antagonist; neoplastic cell; nerve stem cell; novel; outcome forecast; palliative; public health relevance; regenerative; response; self-renewal; stemness; trait; tumor; tumor growth

 DESCRIPTION (provided by applicant): Glioblastomas (GBM) exhibit a remarkable tumor cell heterogeneity, which contributes to the overall regenerative and aggressive disease traits. Recent studies in our laboratory's and others' strongly support the existence of a cellular hierarchy within GBM in which brain tumor initiating cells (BTICs) at the apex are the driving force of disease recurrence and resistance to current therapies. It is imperative to consider the intimate and dynamic interactions between BTICs and their immediate environments in perivascular, hypoxic, and necrotic regions within the tumor. These locations serve as functional niches for BTICs and facilitate access to various factors and interacting partners that promote their growth- and ultimately of the overall tumor. While clinical studies have uncovered high platelet counts as a negative prognostic marker for survival outcomes in GBM patients, there is no study to functionally elucidate a role for platelets in this highly aggressive disease. The proposed studies aim to uncover a biological role for platelets in driving the growth and stemness qualities specifically of BTICs, which have been histologically detected in BTIC-related niches in primary clinical specimens. As location serves a strong purpose within the context of BTICs, successful characterization of potential crosstalk between platelets and BTICs will offer a new clinical perspective into GBM and inform of a novel treatment paradigm to target these specific cell-to-cell interactions. The development of effective therapeutics to disrupt platelets-BTIC interactions may improve the long-term clinical outcomes of GBM patients undergoing current standard therapies.

 描述（由申请人提供）：胶质母细胞瘤（GBM）表现出显著的肿瘤细胞异质性，这有助于整体再生和侵袭性疾病特征。我们实验室和其他实验室的最新研究强烈支持GBM内存在细胞层次结构，其中位于顶点的脑肿瘤起始细胞（BTIC）是疾病复发和对当前治疗耐药的驱动力。必须考虑BTIC与其在肿瘤内血管周围、缺氧和坏死区域中的直接环境之间的密切和动态相互作用。这些位置作为BTIC的功能小生境，并促进获得各种因子和相互作用的伙伴，促进其生长-并最终促进整个肿瘤的生长。虽然临床研究已经发现高血小板计数是GBM患者生存结局的阴性预后标志物，但没有研究从功能上阐明血小板在这种高度侵袭性疾病中的作用。拟议的研究旨在揭示血小板在驱动BTIC特别是BTIC的生长和干性质量方面的生物学作用，BTIC已在主要临床标本中的BTIC相关小生境中进行了组织学检测。由于定位在BTIC的背景下起着重要作用，因此血小板和BTIC之间潜在串扰的成功表征将为GBM提供新的临床视角，并为靶向这些特定细胞间相互作用的新治疗范式提供信息。开发破坏血小板-BTIC相互作用的有效治疗方法可能会改善接受当前标准治疗的GBM患者的长期临床结局。