Fibronectin-binding integrins in angiogenesis

血管生成中纤连蛋白结合整合素

基本信息

批准号：
7729637
负责人：
Judith A VARNER
金额：
$ 30.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729637
关键词：
1-Phosphatidylinositol 3-Kinase Adhesions Adult Angiogenic Factor Antibodies Binding Biological Markers Blood Vessels Bone Marrow Cells Brain Cell Adhesion Molecules Cell Maturation Chemotactic Factors Cytokine Activation Cytoplasmic Tail Development Diagnosis Endothelial Cells Fibronectin Receptors Fibronectins Follicular Dendritic Cells Grant Growth Growth Factor Inflammation Integrin Binding Integrins Interleukin-6 Invaded Lead Malignant - descriptor Mediating Mus Mutation Myeloid Cells Neoplasm Metastasis Neoplasms in Vascular Tissue Normal tissue morphology Pericytes Point Mutation Property Signal Pathway Testing Transforming Growth Factors Tumor Angiogenesis Tumor Immunity Tumor-Derived Vascular Endothelial Growth Factors Vascular Endothelium angiogenesis base cell motility cytokine innovation migration neoplastic cell new growth novel novel strategies novel therapeutics paxillin prevent receptor-mediated signaling tumor tumor growth tumor progression

项目摘要

Angiogenesis, the growth of new blood vessels, promotes tumor growth and metastasis. During the previous grant cycle, we found that the fibronectin receptor integrin α4β1 promotes tumor angiogenesis by distinct endothelial cell- and myeloid cell-mediated mechanisms. Our studies showed that endothelial cell integrin α4β1 promotes tumor angiogenesis and growth. We observed that 1) integrin α4β1 is expressed on growth factor- and tumor-induced but not normal blood vessels; 2) integrin α4 antagonists block endothelial cell migration and survival and suppress developmental and tumor angiogenesis, as well as tumor growth and metastasis; 3) endothelial cell specific deletion of α4 (Tie2Cre+Itga4 loxp/loxp) inhibited angiogenesis, as did an integrin α4 cytoplasmic tail knockin mutation (Itga4Y991A/Y991A) that prevents integrin α4β1 activation, and 4) VEGF-A stimulates endothelial cell integrin α4 activation by inducing the binding of paxillin to the α4 cytoplasmic tail. Our studies indicate that endothelial cell integrin α4β1 may serve as a tumor biomarker and as a target for novel anti-tumor therapies. Our studies showed that integrin α4β1 promotes endothelial cell invasion in tumors, with subsequent tumor angiogenesis, growth and metastasis. We observed that 1) chemoattractants released from tumor cells, such as SDF-1α or VEGF stimulate PI-3-kinase alpha- and paxillin-dependent α4β1 mediated migration of endothelial cells and that 2) antibody antagonists of α4β1 blocked tumor angiogenesis and progression, and 3) mutations that impaired expression or activation of α4β1 (Tie2Cre+Itga4 loxp/loxp and Itga4Y991A/Y991A) blocked tumor angiogenesis, growth and metastasis. Our studies indicate that integrin α4β1 activation in endothelial cells depends on PI3kinase alpha and antagonism of integrin ⟨4®1 activation or function represents a new approach to control tumor progression. We therefore propose to test the hypothesis that integrin α4β1 activation by cytokine-induced signaling pathways is required for endothelial cell-mediated tumor angiogenesis and growth. The specific aims for this proposal are: 1) To identify receptor-mediated signaling pathways by which tumor derived factors activate endothelial cell integrin ⟨4®1 to promote adhesion and invasion, and 2) To evaluate endothelial cell integrin ⟨4®1 to serve as a biomarker for tumor diagnosis and as a target for anti-tumor therapy.

血管生成是新血管的生长，促进肿瘤的生长和转移。在上一个赠款周期中，我们发现纤连蛋白受体整联蛋白α4β1通过不同的内皮细胞和髓样细胞介导的机制促进肿瘤血管生成。我们的研究表明，内皮细胞整联蛋白α4β1促进肿瘤血管生成和生长。我们观察到1）整联蛋白α4β1在生长因子和肿瘤诱导但不是正常血管上表达； 2）整联蛋白α4拮抗剂阻止内皮细胞迁移，存活，并抑制发育和肿瘤血管生成，以及肿瘤的生长和转移； 3）α4（TIE2CRE+ITGA4 LOXP/LOXP）的内皮细胞特异性缺失抑制了血管生成，整联蛋白α4细胞质尾巴敲击蛋白突变（ITGA4Y991A/Y991A）也可以通过α4β1的激活来刺激整合性α4β1激活，并阻止整合性触发α4β1的激活，4）帕克西林到α4细胞质尾巴。我们的研究表明，内皮细胞整联蛋白α4β1可以用作肿瘤生物标志物，也可以作为新型抗肿瘤疗法的靶标。我们的研究表明，整联蛋白α4β1促进肿瘤中的内皮细胞侵袭，随后肿瘤血管生成，生长和转移。 We observed that 1) chemoattractants released from tumor cells, such as SDF-1α or VEGF stimulates PI-3-kinase alpha- and paxillin-dependent α4β1 mediated migration of endothelial cells and that 2) antibody antagonists of α4β1 blocked tumor angiogenesis and progression, and 3) mutations that impaired expression or activation of α4β1 （TIE2CRE+ITGA4 LOXP/LOXP和ITGA4Y991A/Y991A）阻塞肿瘤血管生成，生长和转移。我们的研究表明，内皮细胞中整联蛋白α4β1激活取决于PI3KINASEα和整联蛋白<4®1激活或功能的拮抗作用，代表了一种控制肿瘤进展的新方法。因此，我们建议检验以下假设：内皮细胞介导的肿瘤血管生成和生长需要细胞因子诱导的信号传导途径的整合素α4β1激活。该提案的具体目的是：1）鉴定受体介导的信号传导途径，肿瘤衍生因子激活内皮细胞整联蛋白<4®1以促进粘附性和侵袭，以及2）评估内皮细胞整合蛋白<44®1，以作为肿瘤诊断的生物标记物和抗肿瘤疗法的靶标。