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The Role of Integrin Affinity Modulation during Tumor Angiogenesis

整合素亲和力调节在肿瘤血管生成过程中的作用

基本信息

批准号：
9752370
负责人：
Fadi Emad Pulous
金额：
$ 1.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752370
关键词：
Ablation Actins Acute Adaptor Signaling Protein Adhesives Affinity Amino Acid Substitution Angiogenic Switch Animal Model Automobile Driving Basement membrane Binding Binding Proteins Blood Platelets Blood Vessels Cancer Model Cell Adhesion Cell physiology Cells Chemosensitization Clinical Clinical Trials Co-Immunoprecipitations Complex Conflict (Psychology)Cytoplasmic Tail Cytoskeleton Data Defect Development Disease Disease Progression Disease susceptibility Endothelial Cells Endothelium Exhibits Extracellular Domain Extracellular Matrix Future Genetic Growth Growth Factor Hematopoietic Hemorrhage Impairment In Vitro Integrin alphaVbeta3 Integrin beta Chains Integrin beta3 Integrins Intercellular Junctions Investigation KDR gene Knock-in Knock-in Mouse Laboratories Lead Ligand Binding Ligands Macromolecular Complexes Malignant Neoplasms Mediating Modeling Molecular Molecular Conformation Mus Mutant Strains Mice Neoplasm Metastasis Neoplasms in Vascular Tissue Pathologic Neovascularization Pathology Pathway interactions Pharmacology Phase Play Pre-Clinical Model Primary Neoplasm Process Property Protein Family Publishing Regulation Reporting Role Signal Transduction Site Solid Solid Neoplasm Specificity Structure Talin Tamoxifen Testing Tumor Angiogenesis Vascular Endothelial Growth Factors Work angiogenesis blood vessel development design extracellular in vivo inhibitor/antagonist insight melanoma migration monolayer mouse model mutant neovascularization novel postnatal postnatal development pre-clinical rapid growth retinal angiogenesis subcutaneous tumor tumor growth tumor hypoxia tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

Project Summary: Pathological angiogenesis, the aberrant proliferation and formation of new blood vessels, during tumorigenesis culminates in an “angiogenic-switch” whereby small, avascular tumors enter a state of rapid growth driving disease progression and metastasis. Endothelial cells lining blood vessels in the tumor microenvironment respond to secreted vascular endothelial growth factor (VEGF) and navigate through the extracellular matrix (ECM) during the initial steps of sprouting angiogenesis. The integrin family of proteins modulate new vessel growth by regulating endothelial cell adhesive interactions with the ECM, neighboring endothelial cells at intercellular junctions, and with the basement membrane. Pharmacological blockade of integrins has demonstrated potent anti-tumorigenic effects in pre-clinical models, but clinical trials of this class of inhibitors have failed to show phase-III efficacy demonstrating a need for a greater understanding of integrin signaling. A noteworthy property of integrins is that their affinity for extracellular ligands is regulated through “inside-out” signaling. Talin, a cytoskeletal adaptor protein, binds the β-integrin cytoplasmic tail at two distinct sites, resulting in a conformational change whereby the extracellular domain extends into the ECM to engage ligand. We have previously published that mice expressing a platelet-specific talin1 mutant (talin1 L325R) defective in its capacity to activate integrins exhibit severe defects in platelet integrin activation that lead to a bleeding diathesis. To test the central hypothesis that talin-dependent integrin activation is required for angiogenesis (Aim #1), we have generated inducible endothelial cell-specific talin1 L325R knock-in mice (Fig 1). Induction of talin1 L325R expression during postnatal development caused early lethality and extensive defects in retinal angiogenesis (Fig 2). Interestingly, preliminary work using a B16/F10 murine melanoma model showed reductions in primary tumor size in talin1 L325R mice (Fig 3) while both talin1 L325R and talin1 WT mice exhibited no observable defects in pre-existing vasculature (Fig 5) suggesting the potential specificity of talin- dependent integrin activation for nascent vessel development. We propose to test the requirement of talin- mediated integrin activation for primary tumor growth and tumor angiogenesis. Curiously, several laboratories have reported integrin signaling promotes VEGF/VEGFR2 signaling, a central pathway responsible for angiogenesis during solid-tumor progression. Recent work suggests that stimulation of endothelial cells with VEGF induces an αvβ3-VEGFR2 macromolecular complex that potentiates VEGF signaling. In Aim 2, we will test the requirement of integrin activation during VEGF-mediated angiogenesis in vivo and whether integrin activation is necessary for downstream VEGF/VEGFR2 signal transduction. This work will provide important insight into the relationship between endothelial cell inside-out integrin signaling in angiogenesis and examine the role of talin-dependent inside-out signaling in cross-talk between integrins and VEGF signaling.

项目总结: