Endothelial plasticity in glioma vascularization and therapy resistance

神经胶质瘤血管化和治疗抵抗中的内皮可塑性

• 批准号: 9146967
• 负责人: Yi Fan
• 金额: $ 35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146967
• 关键词: Angiogenic Factor; Area; Blood Vessels; Cell Proliferation; Cell physiology; Cells; Cytotoxic Chemotherapy; Data; Development; Endothelial Cells; Fibroblasts; Fibrosis; Gene Expression Profiling; Genetic; Glioblastoma; Glioma; Goals; Growth; Health; Human; Hypoxia; In Vitro; Investigational Therapies; Knockout Mice; Lead; MMP14 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Mus; Myocardial Infarction; Neoplasms in Vascular Tissue; Outcome; Patients; Permeability; Phenotype; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor; Population; Primary Brain Neoplasms; Process; Proteomics; Radiation; Refractory; Research; Resistance; Role; Smooth Muscle Myocytes; Solid; Solid Neoplasm; Specimen; System; Testing; Therapeutic; Tumor Angiogenesis; VEGFA gene; Vascular Endothelial Cell; Vascularization; acquired treatment resistance; angiogenesis; antiangiogenesis therapy; autocrine; base; cell motility; cell transformation; chemotherapy; cytotoxic; driving force; genetic signature; in vivo; insight; meetings; melanoma; new therapeutic target; novel strategies; programs; radiation response; receptor; research study; stem; stemness; targeted treatment; temozolomide; therapeutic angiogenesis; therapy resistant; tumor; tumor progression; vascular abnormality

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans, distinguished by prominent vascularity and extraordinary vascular abnormality. Most GBM tumors are refractory to conventional cytotoxic therapies. Overgrown, abnormal vasculature characterizes the microenvironment that fuels cancer progression and induces spatially heterogeneous hypoxia and therapeutic resistance in malignant solid tumors. Anti-angiogenic therapies, primarily targeting vascular endothelial growth factor (VEGF)-A and its receptors, have been developed and exploited in recent years; however, the therapeutic benefits are small in GBM, due to acquired treatment resistance and other unidentified mechanisms. Here we show that endothelial cell (EC) plasticity-mediated vascular transformation is critical for aberrant tumor angiogenesis and therapy resistance, therefore serving as a new therapeutic target in GBM. We discover endothelial fibro-transformation (Endo-FT) in GBM vasculature, by which ECs acquire fibroblast phenotypes including high motility and invasiveness to generate excessive abnormal vasculature. Utilizing human specimen and orthotopic, genetic mouse tumor models, our preliminary studies reveal robust Endo-FT in GBM, characterized by EC expression of the mesenchymal markers, and a prominent population of GBM-associated mesenchymal cells with EC origin. Furthermore, our proteomic analysis identifies a critical role of c-Met in Endo-FT, requisite for the vascular abnormality in the GBM microenvironment. c-Met phosphorylation induces matrix metalloproteinase (MMP)-14 expression and Endo-FT. Finally, our in vivo data using EC-specific c-Met knockout mice establish a critical role of c-Met in Endo-FT, cancer growth and progression, and GBM resistance to temozolomide chemotherapy. Based on these results, we hypothesize that Endo-FT is a driving force for aberrant tumor vascularization, and targeting Endo-FT provides a novel strategy to inhibit excessive angiogenesis, normalize tumor vessels, and overcome therapy resistance in GBM. To test this hypothesis, we will 1) determine the in vivo role of c-Met-mediated Endo-FT in tumor hypoxia, glioma progression and therapeutic resistance, and test experiment therapy that combines c-Met inhibition and radiation or chemotherapy in mouse tumor models; 2) define the mechanisms by which HGF/c-Met induces Endo-FT and vascular abnormality with a focus on HGF autocrine and MMP-14 expression; and 3) perform system-wide analysis of the Endo-FT and vascular transformation, focusing on platelet-derived growth factor (PDGF)- and hypoxia-mediated mechanisms. Successful completion of this project may provide alternative insights into aberrant tumor vascularization and lead to development of new anti-angiogenic and vessel normalization strategies for treating GBM.

 描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是人类最常见和最具侵袭性的原发性脑肿瘤，其特征是显着的血管分布和异常的血管异常。促进癌症进展并诱导恶性实体瘤的空间异质缺氧和治疗抵抗的微环境，主要针对血管内皮。近年来，生长因子（VEGF）-A 及其受体得到了开发和利用；然而，由于获得性治疗耐药性和其他未知机制，内皮细胞（EC）的可塑性对 GBM 的治疗效果很小。介导的血管转化对于异常的肿瘤血管生成和治疗耐药至关重要，因此我们在 GBM 血管系统中发现了内皮纤维转化（Endo-FT），从而成为 GBM 的新治疗靶点。 EC 获得成纤维细胞表型，包括高运动性和侵袭性，以产生过度异常的脉管系统。利用人类标本和原位遗传小鼠肿瘤模型，我们的初步研究揭示了 GBM 中强大的 Endo-FT，其特征是 EC 表达间充质标记物和突出的群体。此外，我们的蛋白质组学分析确定了 c-Met 在 Endo-FT 中的关键作用，这是血管必需的。 GBM 微环境中的 c-Met 磷酸化异常诱导基质金属蛋白酶 (MMP)-14 表达和 Endo-FT。 FT、癌症生长和进展以及 GBM 对替莫唑胺化疗的耐药性 基于这些结果，我们发现 Endo-FT 是异常肿瘤血管化和靶向的驱动力。 Endo-FT 提供了一种抑制过度血管生成、使肿瘤血管正常化并克服 GBM 治疗耐药的新策略。为了检验这一假设，我们将 1) 确定 c-Met 介导的 Endo-FT 在肿瘤缺氧中的体内作用，胶质瘤进展和治疗耐药性，并在小鼠肿瘤模型中测试结合 c-Met 抑制和放疗或化疗的实验疗法；2) 确定 HGF/c-Met 诱导 Endo-FT 和血管异常的机制，重点是HGF 自分泌和 MMP-14 表达；3) 对 Endo-FT 和血管转化进行全系统分析，重点关注血小板衍生生长因子 (PDGF) 和缺氧介导的机制。对异常肿瘤血管化的深入了解，并导致开发新的抗血管生成和血管正常化策略来治疗 GBM。