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(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脑肿瘤，以显著的血管和异常的血管异常为特征。大多数基底膜肿瘤对传统的细胞毒治疗是无效的。过度生长的、异常的血管系统是恶性实体肿瘤的微环境的特征，这种微环境助长了癌症的进展，并诱导了空间上的异质性缺氧和治疗抵抗。近年来，主要针对血管内皮生长因子-A及其受体的抗血管生成疗法已被开发和利用；然而，由于获得性耐药和其他机制不明，对GBM的治疗益处很小。在此，我们发现内皮细胞(EC)可塑性介导的血管转化对于异常的肿瘤血管生成和治疗抵抗是至关重要的，因此成为GBM的新的治疗靶点。我们在基底膜血管系统中发现了内皮纤维转化(Endo-FT)，通过这种转化，内皮细胞获得了包括高运动性和侵袭性在内的成纤维细胞表型，从而产生了过度异常的血管。利用人类标本和原位遗传的小鼠肿瘤模型，我们的初步研究揭示了GBM中强大的Endo-FT，其特征是EC表达间充质标志物，并具有显著的EC起源的GBM相关间充质细胞群体。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GBM微环境中血管异常所必需的。C-Met磷酸化可诱导基质金属蛋白酶-14表达和内源性FT。最后，我们使用EC特异性c-Met基因敲除小鼠的体内数据证实了c-Met在Endo-FT、肿瘤生长和进展以及GBM对替莫唑胺化疗耐药中的关键作用。基于这些结果，我们假设Endo-FT是异常肿瘤血管生成的驱动力，靶向Endo-FT为抑制过度的血管生成、正常化肿瘤血管和克服GBM的治疗抵抗提供了一种新的策略。为了验证这一假说，我们将1)确定c-Met介导的Endo-FT在肿瘤缺氧、胶质瘤进展和治疗耐药中的体内作用，并测试c-Met抑制和放化疗相结合的小鼠肿瘤模型的实验治疗；2)确定HGF/c-Met诱导Endo-FT和血管异常的机制，重点关注HGF自分泌和MMP-14的表达；以及3)对Endo-FT和血管转化进行系统分析，重点关注血小板衍生生长因子(PDGF)和缺氧介导的机制。该项目的成功完成可能会为异常肿瘤血管形成提供另一种见解，并导致开发新的抗血管生成和血管正常化策略来治疗GBM。