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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

基本信息

批准号：
9303471
负责人：
Yi Fan
金额：
$ 35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/9303471
关键词：
Abnormal Endothelial Cell 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 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 Pathologic Patients Permeability Pharmacology 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 experimental study genetic signature in vivo insight melanoma new therapeutic target novel strategies programs public health relevance radiation response receptor stem-like cell stemness targeted treatment temozolomide therapeutic angiogenesis therapy resistant transcription factor tumor tumor progression vascular abnormality

项目摘要

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.