Crosstalk Between Platelets and Brain Tumor Initiating Cells in Glioblastoma

 描述(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，这有助于整体的再生性和侵袭性疾病特征。我们实验室和其他实验室最近的研究有力地支持了基底膜中存在细胞层次结构，其中位于顶端的脑肿瘤起始细胞(BTICs)是疾病复发和对当前治疗耐药的驱动力。必须考虑肿瘤内血管周围、缺氧区和坏死区BTICs与其周围环境之间的密切和动态相互作用。这些位置是BTIC的功能区，有助于获得促进其生长的各种因素和相互作用的伙伴--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患者生存结果的负面预后标志，但还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的生长和茎质量方面的生物学作用，特别是在BTIC的组织学上已经在初级临床标本的BTIC相关的壁龛中检测到。由于定位在BTICs中具有很强的作用，成功表征血小板和BTICs之间的潜在串扰将为GBM提供一个新的临床视角，并提供一种新的治疗范例来针对这些特定的细胞间相互作用。开发有效的治疗方法来干扰血小板与BTIC的相互作用可能会改善正在接受当前标准治疗的GBM患者的长期临床结果。

 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.